Immunological Homeostasis of The Eye

Progress in Retinal and Eye Research 33 (2013) 10e27
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Progress in Retinal and Eye Research

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Immunological homeostasis of the eye

Manabu Mochizuki a, *,1, Sunao Sugita a, b,1, Koju Kamoi a,1
a
b
Department of Ophthalmology & Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 26 October 2012
Uveitis is a sight-threatening disease caused by autoimmune or infection-related immune responses.

Studies in experimental autoimmune uveitis and in human diseases imply that activated CD4 T cells,
Th1 and Th17 cells, play an effector role in ocular inammation. The eye has a unique regional immune
system to protect vision-related cells and tissues from these effector T cells. The immunological balance
between the pathogenic CD4 T cells and regional immune system in the eye contributes to the maintenance of ocular homeostasis and good vision. Current studies have demonstrated that ocular parenchymal cells at the inner surface of the blood-ocular barrier, i.e. corneal endothelial (CE) cells, iris
pigment epithelial (PE) cells, ciliary body PE cells, and retinal PE cells, contribute to the regional immune
system of the eye. Murine ocular resident cells directly suppress activation of bystander T cells and
production of inammatory cytokines. The ocular resident cells possess distinct properties of immunoregulation that are related to disparate anatomical location. CE cells and iris PE cells, which are located
at the anterior segment of the eye and face the aqueous humor, suppress activation of T cells via cell-tocell contact mechanisms, whereas retinal PE cells suppress the activation of T cells via soluble factors. In
addition to direct immune suppression, the ocular resident cells have another unique immunosuppressive property, the induction of CD25Foxp3 Treg cells that also suppress the activation of bystander
T cells. Iris PE cells convert CD8 T cells into Treg cells, while retinal PE cells convert CD4 T cells greatly
and CD8 T cells moderately into Treg cells. CE cells also convert both CD4 T cells and CD8 T cells into
Treg cells. The immunomodulation by ocular resident cells is mediated by various soluble or membranebound molecules that include TGF-b TSP-1, B7-2 (CD86), CTLA-2a, PD-L1 (B7-H1), galectin 1, pigment
epithelial-derived factor PEDF), GIRTL, and retinoic acid. Human retinal PE cells also possess similar
immune properties to induce Treg cells. Although there are many issues to be answered, human Treg
cells induced by ocular resident cells such as retinal PE cells and related immunosuppressive molecules
can be applied as immune therapy for refractive autoimmune uveitis in humans in the future.
2012 Elsevier Ltd. All rights reserved.
Keywords:
Uveitis
Experimental autoimmune uveitis
VogteKoyanagieHarada disease
Human T-cell leukemia virus type 1 uveitis
Ocular pigment epithelial cells
Corneal endothelial cells
Effector T-cells
Th 17 cells
Regulatory T cells
Transforming growth factor
Foxp3
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
T cells and intraocular inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.1.
Experimental autoimmune uveoretinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.2.
VogteKoyanagieHarada (VKH) disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.3.
Human T-lymphotropic virus type 1 (HTLV-1) uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Regional defense system in the eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17
3.1.
Ocular resident cells and their direct immune regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.1.1.
Direct T-cell suppression by retinal PE cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
3.1.2.
Direct T-cell suppression by iris PE cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
* Corresponding author. Tel.: 81 3 5803 5296; fax: 81 3 5803 0145.

E-mail address: m.manabu.oph@tmd.ac.jp (M. Mochizuki).
1
Percentage of work contributed by each author in the production of the manuscript is as follows: Manabu Mochizuki: 50%; Sunao Sugita: 25%; Koju Kamoi: 25%.
1350-9462/$ e see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.preteyeres.2012.10.002
M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27
11
3.1.3.
Direct T-cell suppression by CE cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Regulatory T cells generated by ocular resident cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3.2.1.
Regulatory T cells generated by ocular PE cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
3.2.2.
Regulatory T cells generated by CE cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
3.2.3.
Regulatory T cells in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
3.2.
4.
1. Introduction
2. T cells and intraocular inammation
Uveitis, an intraocular inammatory disorder, is a sightthreatening disease caused by autoimmune mechanisms or infectious agents. Although the pathogenesis of autoimmune uveitis
is still controversial, the involvement of auto-antigens or autoantibodies had been speculated for years prior to the discovery of
a pathogenic retinal auto-antigen by Wacker and colleagues (Wacker
and Lipton, 1965; Wacker et al., 1977). Since then, the understanding
of pathogenic mechanisms of autoimmune uveitis has greatly progressed. Investigations in animal models have shown that active
CD4 T cells (De Kozak et al., 1976; Faure et al., 1977; SalinasCarmona et al., 1982; Gregerson and Abrahams, 1983; Mochizuki
et al., 1984, 1985a; Caspi et al., 1988, 1996; Sonoda et al., 2003;
Amadi-Obi et al., 2007), particularly Th1 and Th17 cells (Amadi-Obi
et al., 2007), inltrate the eye and play a central role in the pathogenesis of autoimmune uveitis. In humans, activated CD4 T cells
also contribute to the immunopathogenic mechanisms of various
diseases, such as VogteKoyanagieHarada disease (Sugita et al.,1996,
2006d; Yamaki et al., 2000a, 2000b) and human T-lymphotropic
virus type 1 uveitis (Sagawa et al., 1995; Ono et al., 1997).
The eye is protected from invasive pathogens by two systems, an
anatomical barrier and an immunological barrier. The bloodeocular
barrier anatomically blocks harmful pathogens from invading the
eye from the peripheral bloodstream and protects sight-related cells
and tissues. Pigment epithelial (PE) cells of the iris, ciliary body, and
retina, vascular endothelial cells of the retina, and corneal endothelial (CE) cells are important components of the bloodeocular
barrier. Once the bloodeocular barrier is disrupted, another
defense system, the regional immune system of the eye, suppresses
pathogenic T cells and protects the eye. Because of this unique
feature, the eye is considered to be an immune-privileged site like
the brain and testes. Streilein and colleagues provided the rst
evidence of ocular immune privilege (Streilein et al., 1980; Streilein,
2003). A typical example of ocular immune privilege is anterior
chamber-associated immune deviation (ACAID) proposed by Kaplan
and Streilein (Kaplan, 1977; Kaplan and Streilein, 1978). Ocular
resident cells at the inner surface of the bloodeocular barrier, such
as iris PE cells, ciliary body PE cells, retinal PE cells, and CE cells, can
suppress the activation of bystander CD4 T cells (Yoshida et al.,
2000; Ishida et al., 2003; Sugita and Streilein, 2003; Sugita et al.,
2004, 2006a, 2009b, 2009c, 2011b, 2012; Futagami et al., 2007;
Horie et al., 2009). Furthermore, these ocular resident cells have the
unique capacity to convert T cells into regulatory T (Treg) cells,
which suppress the activation of bystander T cells (Sugita et al.,
2006b, 2006c, 2007, 2008, 2009a, 2010a, 2011a; Yamada et al.,
2010; Horie et al., 2010). Thus, a balance between activated CD4
T cells in the eye and ocular resident cells maintains the homeostasis
of the eye.
In this review article, we focus on (1) the role of activated CD4 T
cells in uveitis and (2) the role of the regional immune system in
the maintenance of ocular homeostasis, with special attention
given to cellular and molecular mechanisms.
2.1. Experimental autoimmune uveoretinitis

The search for pathogenic mechanisms and auto-antigens in
autoimmune uveitis was conducted for many years until Wacker
and colleagues rst reported a retinal auto-antigen isolated from
water-soluble fractions of bovine retina (Wacker et al., 1977).
The antigen was localized to the photoreceptor layer of the retina
and the pineal gland. Immunization of the antigen in complete
Freunds adjuvant at a site away from the eye induced inammation in both eyes and the pineal gland. The antigen was named
retinal soluble antigen (S antigen), and the animal model was
designated as experimental autoimmune uveoretinitis (EAU).
Later, it was found that EAU is also induced by other retinal antigens, such as interphotoreceptor retinoid-binding protein (IRBP)
(Gery et al., 1990), phosducin (Dua et al., 1992), and recoverin (Gery
et al., 1994), and synthetic peptides of these antigens. EAU can be
induced in guinea pigs (De Kozak et al., 1976; Wacker et al., 1977),
rats (De Kozak et al., 1981), mice (Caspi et al., 1988; Iwase et al.,
1990), and monkeys (Nussenblatt et al., 1981a). Early studies
(Salinas-Carmona et al., 1982; Mochizuki et al., 1985a, 1985b;
Nussenblatt et al., 1981b; Mochizuki and deSmet, 1994) demonstrated that EAU is an organ-specic autoimmune disease mediated by T cells, particularly CD4 T cells. Much later, the successful
induction of EAU in mice (Caspi et al., 1988) allowed us to dissect
the immunological mechanisms of EAU by using transgenic and
knockout (KO) mice.
The development of EAU in mice can be studied with conventional induced models or more recently developed spontaneous
models. In induced EAU models, mice are immunized with a retinal
antigen in complete Freunds adjuvant (CFA) (Agarwal and Caspi,
2004). This immunization activates antigen-presenting cells
(APCs), such as dendritic cells (DCs) and macrophages, through the
innate immune response and activates retinal antigen-specic T
cells in skin-draining lymph nodes. The spontaneous EAU models
utilize transgenic mice and do not require active immunizations
and adjuvant. In a representative spontaneous EAU model, transgenic mice expressing the neo-self antigen, hen egg lysozyme (HEL)
under the retinal-specic IRBP promoter are crossed to the 3A9
HEL-specic CD4 T cell receptor (TCR)-transgenic line (Lambe
et al., 2007). A more recently developed spontaneous EAU model
uses transgenic mice (R161H) that express a TCR specic to the
major uveogenic epitope of IRBP (Chaon et al., 2012). The spontaneous models are much more similar to human uveitis than the
induced models in terms of clinical course. Investigations utilizing
the induced or spontaneous EAU models have revealed the cellular
and molecular mechanisms of immune regulation that lead to
ocular immunity and tolerance (Fig. 1).
Numerous T cells cannot escape thymic selection due to death
by neglect (the elimination of T cells with no afnity to autoantigen) or negative selection (the elimination of T cells with high
afnity to auto-antigen). This central tolerance is controlled by the
12
Fig. 1. CD4 T cell differentiation in EAU: central, peripheral, and regional mechanism. Positively selected retinal antigen-specic CD4 T cells play a central role in ocular immunity
and tolerance. Danger signal (PAMPs and DAMPs) interacts with PPRs on APCs such as DCs, which leads to naive T cell activation, clonal expansion, differentiation into effector T cell.
Proinammatory cytokine and chemokine contribute to the breakdown of RBB. Accordingly, activated/differentiated CD4 T cells migrate and inltrate into the eye, which results in
EAU. Immune cells such as immature DCs, nTregs, and iTregs induce peripheral tolerance. Anergy has a role in tolerizing mechanism. Resident PE cells and CE cells are main players
in regional tolerance of the eye. mTEC: thymic medullary epithelial cell, AIRE: autoimmune regulator, DC: dendritic cell, PAMPs: pathogen-associated molecular patterns, DAMPs:
damage-associated molecular patterns, PRRs: pattern recognition receptors, TLR: toll like receptor, APC: antigen-presenting cell, IL: interleukin, Th: T helper cell, Treg: regulatory T
cell, BOB: bloodeocular barrier, EAU: experimental autoimmune uveoretinitis, PE: pigment epithelium, CE: corneal endothelium, ACAID: anterior chamber associated immune
deviation.
autoimmune regulator AIRE, which is responsible for the ectopic

expression of tissue-restricted auto-antigens including retinal autoantigens in the thymus (Egwuagu et al., 1997; Anderson et al., 2002;
Zhang et al., 2003; Ham et al., 2004; Takase et al., 2005; Lambe et al.,
2007). Positively selected and weakly auto-reactive T cells can cause
inammation. In other words, escaped retinal antigen-specic
CD4 T cells play a central role in EAU models. Natural regulatory
T cells (nTregs) are also generated in the thymus and have potentially suppressive effects on autoimmunity (Sakaguchi and
Sakaguchi, 2005). EAU is exacerbated when nTregs are depleted
(Avichezer et al., 2003; Grajewski et al., 2006). nTregs and effector T
cells have the same antigenic specicity as they are both educated
and positively selected in the thymus (Sakaguchi and Sakaguchi,
2005; Grajewski et al., 2006). Therefore, nTregs target multiple
antigens of the eye and are important for peripheral tolerance and
regional tolerance of the eye.
According to molecular mimicry theory, antigen-specic T cells,
which escape nTreg patrol, are primed in the periphery by microbial stimuli (Shinohara et al., 1990; Singh et al., 1992; Wildner and
Diedrichs-Moehring, 2005). Pathogens, such as microbial components, express pathogen-associated molecular patterns (PAMPs)
and interact with innate pattern recognition receptors, such as tolllike receptors (TLRs) (Kawai and Akira, 2005), on APCs.
TLRs 1e11 in humans and TLRs 1e13 in mice have been identied and many of their ligands have been found (Kawai and Akira,
2010). TLRs expressed on APCs, such as DCs and macrophages,
play a critical role in linking innate immunity with adaptive
immunity. The TLReTLR ligand interaction promotes the maturation of APCs through the production of pro-inammatory cytokines
and the up-regulation of co-stimulatory and MHC molecules. The
TLReTLR ligand interaction also allows APCs to become efcient in
the presentation of specic antigens to naive T cells (Janeway and
Medzhitov, 2002; Akira and Takeda, 2004; Pulendran, 2005). The
TLReTLR ligand signaling is moderated by the adaptor molecule
MyD88, which activates NF-kB and other signaling pathways to
produce inammatory cytokines. Both MyD88-dependent and
MyD88-independent pathways participate in the pathogenesis of
autoimmune diseases (Kawai and Akira, 2007). Although escaped
self-specic cells circulate without activation under healthy

conditions, bacterial infection activates these cells and converts
them into pathogenic effector cells through the TLReTLR ligand
system (Fujimoto et al., 2006, 2008). MyD88 KO mice, but not mice
lacking TLR2, -4, or -9, had impaired EAU development (Su et al.,
2005). The redundancy of TLR2, -3, -4, and -9 in the adjuvant
effect is required to induce EAU (Fang et al., 2010).
Some TLRs, such as TLR1/2, 2/6, -4, and -5, respond to bacterial
proteins, whereas other TLRs, such as TLR3, -7, -8, and -9, mainly
respond to bacterial and viral nucleic acids. All TLRs have been
detected at the mRNA level in eye tissues, and the most widely
expressed TLR in the eye is TLR4, which is expressed in the cornea,
conjunctiva, uvea, retina, and sclera (Chang et al., 2006).
Ocular resident cells such as RPE cells, microglia, and astrocytes
have the potential to act as APCs (Percopo et al., 1990; Broderick
et al., 2002; Jiang et al., 2008, 2009). Retinal astrocytes allow
responder T cells to induce uveitis in mice when activated by TLR3
ligand, polyinosinic-polycytidylic acid, TLR4 ligand, lipopolysaccharide (Jiang et al., 2009), NOD2, and TLR2 ligand (Jiang et al.,
2012).
Damage-associated molecular pattern molecules (DAMPs), such
as heat shock proteins and S100 proteins, are released by stressed
cells and bind to DAMPs receptors (Rubartelli and Lotze, 2007).
PAMPs and DAMPs act as danger signals that trigger innate
immunity. Induced models of EAU require immunization with
retinal antigen and adjuvant (pertussis toxin and/or CFA, which
contains heat-killed tuberculosis bacteria). This bacterial component triggers pattern recognition receptors on innate immune cells
such as DCs and stimulates the auto-pathogenic effector pathway in
EAU. Broad-spectrum antibiotic treatment, which depletes the
commensal bacterial ora, inhibits spontaneous EAU, which might
imply the existence of crosstalk between commensal microbiota in
the gut and uveitis in the eye (Chaon et al., 2012) and might also be
clinical evidence of the danger theory.
The main function of DCs is to initiate T-cell-mediated immunity. DCs support naive T-cell activation, clonal expansion, and
differentiation into effector and memory cell (Bousso, 2008).
However, immature DCs in steady state lead to tolerance (Steinman,
2001). Immature DCs have the potential to expand nTreg cells in

peripheral tolerance. This expansion is mediated by the release of
suppressive cytokines such as IL (interleukin)-10 and transforming
growth factor (TGF)-b. Therefore, the administration of immature
DCs suppresses induced and spontaneous EAU (Jiang et al., 2003;
Kamoi et al., 2011; Klaska et al., 2012). Interestingly, the targeted
delivery of self-antigen to specic DC subsets can promote tolerance or immunity in EAU, depending on the DC-specic surface
molecule (Kamoi et al., 2012).
T cells, macrophages, and neutrophils inltrate eye tissues such
as the choroid and retina during the acute phase in EAU (De Kozak
et al., 1978; Dick et al., 1995; McMenamin et al., 1993). Macrophages
play a critical role in tissue destruction (Pouvreau et al., 1998;
Forrester et al., 1998; Dick, 2000). Macrophages that cross the
blooderetinal barrier and inltrate the retina release mediators
such as nitric oxide synthase (NOS)-2 and TNF-a that can cause
severe retinal damage (Miura-Takeda et al., 2008). The activation of
recruited non-antigen-specic macrophages and neutrophils has
an effect on the inammatory function of Th1 and Th17 cells (Kerr
et al., 2008).
The normal retina contains myeloid-derived macrophages and
microglia (Broderick et al., 2000; Dick et al., 1995; Gregerson et al.,
2004; Penfold et al., 1991), which act as a bridge between innate
and adaptive immunity by responding to signals from pattern
recognition receptors such as TLRs and modulating Th-cell stimulation. However, as an opposite function, the inltration of myeloid
cells has the potential to suppress T-cell activation and proliferation
via nitric oxide- and prostaglandin-mediated pathways (Raveney
et al., 2009, 2010).
Effector T cells, especially Th1 and Th17 cells, play a pathogenic
role in EAU (Caspi, 2010). Adoptive transfer of polarized Th1 and
Th17 cells into a naive recipient induces EAU (Shi et al., 2008; Cox
et al., 2008). EAU induced by IRBP and CFA is IL-17 dependent, but
EAU induced with antigen-pulsed DCs requires IFN-g-producing
effector T cells (Luger et al., 2008; Tang et al., 2007). In induced EAU
models, Th17 is thought to play a central role in the pathogenesis of
ocular inammation. However, an analysis of a spontaneous EAU
model (R161H mice) crossed with IFN-g KO mice indicated that
Th17 might be less pathogenic than currently believed (Chaon et al.,
2012). Taken together, there is a great deal of evidence that Th1 and
Th17 cells contribute to the immune-pathogenesis of EAU (AmadiObi et al., 2007). More recently, the roles of Th9 cells expressing IL-9
and Th22 cells expressing IL-22 have been examined in EAU. Th9
cells in EAU retain IL-9 production for a brief period, but have
unique functions in the ocular immune system (Tan et al., 2010). IL22 induces regulatory CD11b APCs to convert pathogenic T cells
into Tregs, so that IL-22 can reduce the severity of EAU and decrease
the numbers of Th1 and Th17 cells (Ke et al., 2011).
gd T cells also participate in ocular inammation. gd T cells can
either upregulate (Spahn et al., 1999; Rajan et al., 2000; Odyniec
et al., 2004; Tagawa et al., 2004) or downregulate (DSouza et al.,
1997; Tsuchiya et al., 2003; Uezu et al., 2004) adaptive immune
responses. gd T cells have a stronger effect on Th17-type autoreactive T cells than Th1-type autoreactive T cells (Cui et al., 2009;
Nian et al., 2010). Nonactivated gd T cells have little effect on ab T
cells, whereas activated gd T cells promote the activation of ab T
cells and enhance EAU development (Nian et al., 2011).
The mechanism for trafcking self-antigen from the eye is
unknown. However, T cells must be activated in the peripheral
lymph nodes or spleen before they inltrate the retina and cause
inammation. The removal of the eye-draining lymph node prior to
corneal transplant prevents corneal graft rejection (Kuffov et al.,
2008). This result indicates that self-antigen is trafcked through
the eye-draining lymph node. Other evidence of antigen trafcking
via lymphatic drainage is that Treg expansion in the eye-draining
13
lymph node down-regulates pathogenic cells and suppresses

ocular inammation in the spontaneous EAU model (Kamoi et al.,
2011). There are candidate resident major histocompatibility
complex (MHC) II-expressing APCs in the retina that might activate
T cells to produce cytokines (Jiang et al., 1999). Furthermore, T cells
accumulate around the 33D1 cells in the retina at the peripheral
margins and around the optic nerve at the onset of EAU (Xu et al.,
2007). Another explanation is that CD45 cells derived from the
circulation are sufcient to provide APC function, even without eyeresident APCs (Gregerson et al., 2004). Anergy is a tolerizing
mechanism that is induced when peripheral self-antigen presentation occurs in the absence of immunogenic co-stimulation
(Schwartz, 2003; Appleman and Boussiotis, 2003; van Parijs et al.,
1998). Typically, naive T cells encountering antigen in tissuedraining lymph nodes undergo an initial burst of proliferation followed by deletion or anergy. The lack of antigen presentation in the
eye-draining lymph nodes results in a lack of T-cell anergy, which
leads to ocular inammation (Lambe et al., 2007).
Activated retinal antigen-specic T cells are thought to migrate
into the eye from the eye-draining lymph node and/or spleen. The
migration and recruitment of inammatory cells are controlled by
adhesion molecules, chemokines, and chemokine receptors. In EAU,
integrin very late activation antigen-4 (Martn et al., 2005),
lymphocyte function-associated antigen 1, intercellular adhesion
molecule 1 (Whitcup et al., 1993), CD44 (Xu et al., 2002), the CXC
chemokine receptor (CXCR) 3 (Chen et al., 2004), and CXCR5 (Crane
et al., 2006) are molecules responsible for the migration. After the
migration, inltrating T cells are controlled by regional mechanisms
of the eye. As nTregs and the effector T cells share the same antigenic specicity, regional immunity and tolerance that target the
same retinal antigen surely exist together in the eye (Gregerson
et al., 2009).
Although EAU is considered to be an animal model for uveitis in
humans, the clinical manifestations and histopathology of EAU are
not exactly the same as those in human disease. Recent research
has shown the critical role of TRL4 in EAU, but single nucleotide
polymorphisms in TLR4 are not important for the development of
uveitis in patients with sarcoidosis (Asukata et al., 2009). Thus,
there are limitations to the application of ndings from EAU to
human diseases. However, studies of EAU indicate that CD4 T cells
play a critical role in ocular immunity and tolerance. Therefore, we
studied the role of CD4 T cells in VogteKoyanagieHarada disease,
which is a prototype of autoimmune uveitis, and uveitis associated
with human T-lymphotropic virus type 1 infection.
2.2. VogteKoyanagieHarada (VKH) disease
VKH disease was rst described by a dermatologist (Vogt, 1906)
in a case report of a patient with poliosis, vitiligo, and uveitis. More
precise ocular manifestations were later described by Koyanagi
(1914) and Harada (1926). The disease is a non-traumatic bilateral
uveitis that is common in pigmented ethnic groups, such as the
Japanese, but rare in non-pigmented ethnic groups, such as
Caucasians. In the early acute stage of the disease, diffuse choroiditis is the primary lesion, as described by Koyanagi (1914) and
Harada (1926) and as demonstrated in the histopathology of ocular
lesions reported by Inomata (1989). In this early stage, patients
develop bilateral uveitis (Fig. 2A, B) together with systemic symptoms such as headache, nausea, tinnitus, and hearing disturbance.
Another characteristic feature of this disease is depigmentation in
pigment-containing tissues such as sunset glow fundus of the eye
(Fig. 2C, D), vitiligo, alopecia, and poliosis (Fig. 3) in the late stage of
the disease. Because of these clinical and histopathological features,
VKH disease is considered to be an autoimmune disease against
melanocytes. However, the pathogenic auto-antigen was unknown
14
Fig. 2. Ocular fundus photograph of a patient with VogteKoyanagieHarada disease (18-year-old woman) (A) Right eye: 6 days after onset, 6 April 2004 (BCVA 0.2). (B) Left eye: 6
days after onset, 6 April 2004 (BCVA 0.3). (C) Right eye: 11 months after onset, 5 March 2005, exhibiting sunset glow fundus with choroidal neovascularization (BCVA 0.08). (D)
Left eye 11 months after the onset, 5 March 2005, exhibiting sunset glow fundus with chorioretinal atrophy and pigment migration (BCVA 0.8). BCVA: best corrected visual acuity.
until Yamaki et al. (2000a, 2000b) established an animal model of

VKH disease by immunizing animals with tyrosinase, which is
a melanocyte-associated antigen and an enzyme related to melanin
synthesis. Tyrosinase-immunized animals developed bilateral
uveitis 2 weeks after immunization, followed by depigmentation in

the skin and in the choroid resembling sunset glow fundus 8 weeks
after the immunization. More importantly, peripheral CD4 T cells
from patients with VKH disease responded to a tyrosinase peptide.
Fig. 3. Depigmentation in VogteKoyanagieHarada disease (A) Alopecia in a 12-year-old girl 3 months after onset (B) Poliosis of eye lash in the same patient as (A), (C) Vitiligo in
a 70-year-old woman 2 years after onset.
To determine if ocular inltrating lymphocytes are sensitized to the

tyrosinase antigen, we assayed the lymphocyte response to
a tyrosinase peptide, tyrosinase450e462, by using T-cell clones
established from inltrating cells in the eyes of patients with VKH
disease and other clinical entities of uveitis (Sugita et al., 2006d).
CD4 T-cell clones established from VKH disease, but not from
Behets disease and sarcoidosis, responded to the tyrosinase450e
462 peptide. The T-cell clone from VKH disease did not respond to
control antigen, an inuenza virus peptide. The response was
strictly dependent on the concentration and structure of the
peptide, indicating that CD4 T cells of VKH disease, but not of other
types of uveitis, are sensitized to and respond to tyrosinase peptide.
However, the molecular mechanisms by which CD4 T cells of VKH
patients are sensitized to tyrosinase are still unknown. We
hypothesized that exogenous pathogens, such as a virus, might
have structural homology with the tyrosinase peptide. GeneBank
data analysis disclosed only one exogenous antigen, cytomegalovirus envelope glycoprotein H290e302 (CMV-egH290e302), that
shared structural homology with the tyrosinase450e462 peptide. Six
amino acids in the 13-amino acid tyrosinase peptide had homologs,
and the sequence was an essential motif recognized by HLA-class II
antigen. VKH disease is signicantly associated with HLA-class II
antigen, HLA-DR4, in many ethnic groups. We further studied
whether CD4 T cells of VKH patients responded to both
tyrosinase450e462 and CMV-egH290e302 in culture. Peripheral blood
mononuclear cells from patients with VKH disease, but not from
patients with other types of uveitis or healthy donors, responded to
both tyrosinase450e462 and CMV-egH290e302. More importantly,
CD4 T-cell clones established from ocular inltrating cells of VKH
disease reacted to both tyrosinase450e462 and CMV-egH290e302 and
produced inammatory cytokines.
In the mimicry phenomenon, T cells specic against microbial
products recognize and react to autologous tissue molecules
(Oldstone, 1998; Barnaba and Sinigaglia, 1997). The phenomenon
was investigated in EAU, and several microbial molecules that
sufciently cross-react with uveitogenic antigens were identied
(Singh et al., 1989a, 1989b, 1990). T cells stimulated with mimicry
peptides from retinal auto-antigens could penetrate the oculare
blood barrier and cause intraocular inammation (Wildner and
Diedrichs-Mhring, 2003, 2004).
The TLReTLR ligand system plays a crucial role in triggering
innate immunity. From the standpoint of the danger theory, it has
been revealed that TLR9 recognizes unmethylated cytidinephosphate guanosine DNA motifs that are frequently present in
viruses including CMV. However, single nucleotide polymorphisms
in the TLR9 gene were not signicantly associated with susceptibility to VKH (Ito et al., 2011). Based on studies conducted by
ourselves and others, one of the most critical aspects of VKH
pathogenesis can be explained by molecular mimicry theory but
not by the danger theory, which does not consider molecular
structure.
The molecular mechanisms of VKH disease are summarized in
Fig. 4. Following CMV infection, CD4 T cells of the infected patient
are sensitized to CMV-egH290e302 peptide. A tyrosinase450e462
peptide expressed on the melanocytes in the eye, meninges, and
skin is recognized by the CMV-sensitized CD4 T cells due to the
molecular mimicry between the two peptides. This recognition
causes the inammatory reaction characteristic of VKH disease.
Thus, the pathogenesis of VKH disease highlights the importance of
CD4 T cells in human autoimmune uveitis.
2.3. Human T-lymphotropic virus type 1 (HTLV-1) uveitis
A signicant role for CD4 T cells in human uveitis has been
further highlighted in another type of uveitis associated with a viral
15
Fig. 4. Hypothesis of molecular mechanisms of VogteKoyanagieHarada disease. The

gure is reproduced (Mochizuki, 2009, Fig. 6) with permission. CMV: cytomegalovirus.
infection, HTLV-1 uveitis. HTLV-1 is a human retrovirus, an RNA

virus that encodes an RNA-dependent DNA polymerase that
translates the viral RNA into a DNA provirus. The provirus is then
integrated into the T-cell genome. HTLV-1 can cause adult T-cell
leukemia and T-cell lymphoma when the integration is monoclonal
(Hinuma et al., 1981; Yoshida et al., 1982, 1984; Yamaguchi et al.,
1984). If the integration is polyclonal, it causes an inammatory
disorder in the central nervous system, tropical spastic paraparesis
(Gessain et al., 1985). The virus is endemic in the Caribbean islands,
parts of central Africa and southwestern Japan (Mochizuki et al.,
1996). A causative relationship for HTLV-1 and uveitis was
demonstrated by a series of sero-epidemiological, virological, and
clinical surveys performed in southwestern Japan (Miyakonojo)
(Mochizuki et al., 1992a, 1992b; Yamaguchi et al., 1994; Sagawa
et al., 1995; Masuoka et al., 1995; Ono et al., 1995, 1997, 1998).
The HTLV-1 seroprevalence in patients with idiopathic uveitis of
unknown etiology was signicantly higher than that of two control
groups (patients with non-uveitis ocular diseases, such as cataracts
and glaucoma, and patients with uveitis of a dened etiology, such
as Behets disease and sarcoidosis) (Mochizuki et al., 1992a, 1992b;
Mochizuki, 2009) (Fig. 5). The seroprevalence in the control groups
Fig. 5. Seroepidemiology of HTLV-1 in an endemic area. The gure is reproduced

(Mochizuki, 2009, Fig. 7) with permission. -: Patients with idiopathic uveitis without
dened etiology ,: Patients with uveitis with dened etiology B: Patients with nonuveitis ocular diseases.
16
increased with patient age, which was in accordance with the age
distribution of HTLV-1 seroprevalence in healthy blood donors. In
contrast, the HTLV-1 seroprevalence in patients with idiopathic
uveitis was extremely high, even in young patients (Fig. 5). A
similar result was found in Kurume, Japan, an area in which HTLV-1
is less endemic. The odds ratio of idiopathic uveitis for HTLV-1
infection was estimated to be 11.0 in Miyakonojo and 7.8 in Kurume (Mochizuki et al., 1992b). Uveitis in HTLV-1 carriers is characterized by intermediate uveitis with vitreous opacities (Fig. 6)
(Yoshimura et al., 1993; Takahashi et al., 2000). We compared
ocular manifestations of idiopathic uveitis to seropositivity for
HTLV-1 (Yoshimura et al., 1993). The HTLV-1-seropositive group
had a signicantly higher incidence of oaters, vitreous opacities,
retinal vasculitis, and intermediate uveitis than the seronegative
patients (P < 0.05). This uveitis was not an ocular complication of
adult T-cell leukemia or tropical spastic paraparesis, because the
patients were asymptomatic HTLV-1 carriers; no patients developed adult T-cell leukemia, and only a few patients developed
tropical spastic paraparesis (Takahashi et al., 2000). These seroepidemiological and clinical data indicate that uveitis in HTLV-1
asymptomatic carriers is a distinct clinical entity caused by HTLV1 infection, and the disease was designated as HTLV-1 uveitis or
HTLV-1-associated uveitis.
Inammatory cytokines produced by HTLV-1-infected CD4 T
cells play an important role in the pathogenesis of HTLV-1 uveitis.
Inltrating cells in the eyes of HTLV-1 uveitis patients are CD3 T
cells (Ono et al., 1997). Polyclonal use of T-cell receptor a for HTLV1-infected T cells in the eye indicates that inltrating cells are not
malignant leukemic cells, but inammatory T cells (Masuoka et al.,
1995). Provirus DNA of HTLV-1 was detected by polymerase chain
reaction assay in the aqueous humor of almost all HTLV-1 uveitis
patients (37 of 38 patients), but not in patients with uveitis of
other etiologies who were seropositive for HTLV-1 (Ono et al.,
1997). Viral particles with a 103-nm diameter were detected by
transmission electron microscope in CD4 T-cell clones established
from inltrating cells in the eyes of HTLV-1 uveitis patients, and
HTLV-1 envelope protein was detected on the T-cell clones by
immunouorescence methods (Sagawa et al., 1995). The provirus

load of HTLV-1 in peripheral blood was signicantly higher in
HTLV-1 uveitis patients than in asymptomatic carriers without
uveitis (Ono et al., 1995), and the provirus load in the eyes of HTLV1 uveitis patients was signicantly associated with the intensity of
intraocular inammation (Ono et al., 1998). Furthermore, the HTLV1 provirus load was signicantly higher in the eye than in the
peripheral blood (Ono et al., 1997), indicating that HTLV-1-infected
CD4 T cells signicantly accumulate in the eyes of the patients.
Lastly, HTLV-1-infected CD4 T-cell clones established from the
eyes of HTLV-1 uveitis patients produced large amounts of
inammatory cytokines such as IL-1, IL-6, IL-8, TNF-a, and interferon-g, and this cytokine production was suppressed by adding
corticosteroid to the culture medium (Sagawa et al., 1995). This
result is consistent with clinical observations that corticosteroids
are an effective treatment for HTLV-1 uveitis.
HTLV-1 infection reduces the fraction of naive T cells (Yasunaga
et al., 2001) but increases the fraction of CD4CD45RO effector/
memory cells (Richardson et al., 1990). Infected T cells stimulated
with antigen presentation from DCs proliferate, triggering HTLV-1
replication. During the replication stage, a viral protein, Trance
activator X (Tax), activates NF-kB and up-regulates the expression
of IL-2 and IL-2 receptors, which promotes the growth of infected
cells (McGuire et al., 1993; Boxus et al., 2008). NF-kB also activates
the long terminal repeat of the HTLV-1 genome, which further
enhances viral replication (Robek and Ratner, 1999). The replicated
virus induces a host immune response, and infected cells are
eliminated by the induction of cytotoxic T lymphocytes (CTLs)
specic for HTLV-1 Tax. CTLs predominantly recognize the viral
antigen HTLV-1 Tax and contribute to the pathogenesis of chronic
inammatory diseases (Jacobson et al., 1990; Kannagi et al., 1991).
Epigenetic mechanisms can reduce the amount of viral replication,
which leads to latent infection by allowing the virus to escape from
acquired immune responses (Ego et al., 2002; Kamoi et al., 2006;
Yamamoto et al., 2011). Investigating the latent infection is critical
to identify the pathogenesis of HTLV-1 uveitis because it can occur
in asymptomatic carriers.
Fig. 6. Color pictures (A, B) and uorescein angiographic pictures (C, D) of ocular fundus in a patient with HTLV-1 uveitis (60-year-old woman). (A) Right eye with moderate vitreous
opacities (BCVA 0.8). (B) Left eye without inammation (BCVA 1.5). (C) Fluorescein angiography of right eye showing mild dye leakage from the optic disc and retinal blood
vessels. (D) Fluorescein angiography of the left eye with normal appearance.
The recent discovery of Tregs has helped elucidate the inammatory mechanisms in HTLV-1-infected hosts. Tregs suppress the
CTL response in HTLV-1-infected patients, and reduced Foxp3
expression and Treg function was found in CD4CD25 T cells from
patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (Hayashi et al., 2008; Michaelsson et al., 2008; Oh et al.,
2006; Ramirez et al., 2010; Yamano et al., 2005). Overexpression
of HTLV-1 Tax reduced Foxp3 expression and inhibited the
suppressive function of Treg cells in vitro (Yamano et al., 2005).
Signicantly decreased numbers of CD4CD25Foxp3 Treg cells
were observed in transgenic mice expressing HTLV-1 Tax (Ohsugi
and Kumasaka, 2011). In addition, a newly identied virus
protein, HTLV-1 basic leucine-zipper factor (HBZ), has the potential
to suppress Tax-mediated transcription activation of the long
terminal repeat (Yasunaga and Matsuoka, 2011). CD4Foxp3 Treg
cells in HBZ transgenic mice were functionally impaired (Satou
et al., 2011). Taken together, these results indicate that HTLV-1
Tax and HBZ must be responsible for immune disturbances in
HTLV-1-infected patients; therefore, these molecules are being
investigated as target molecules for the treatment of HTLV-1 uveitis
(Kamoi and Mochizuki, 2012). HTLV-1 uveitis is caused by the
alternation of immune status and the cytokine production from
HTLV-1-infected nonmalignant cells (Kamoi and Mochizuki, 2012).
Many collaborators with immune cells around infect CD4 T cells
contribute to the pathogenesis of HTLV-1 uveitis, which highlighs
the signicant role played by CD4 T cells in human uveitis.
3. Regional defense system in the eye
Under conditions of intraocular inammation in experimental
animals and humans, activated CD4 T cells inltrate the eye and
cause immune responses and inammation, which damage visionrelated cells and tissues. However, the eye has a unique immune
system to protect important cells and tissues from activated
effector CD4 T cells. Streilein and colleagues provided the rst
evidence that ocular parenchymal cells participate in ocular
immune privilege (Streilein, 2003). They demonstrated a phenomenon termed anterior-chamber-associated immune deviation
(ACAID), in which tumor cells inoculated in the anterior chamber of
the eye induce antigen-specic suppression of the cellular immune
response but not the humoral immune response. The immune
deviation arises when antigens are placed not only in the anterior
chamber (Streilein, 1987), but also in the vitreous cavity (Jiang and
Streilein, 1991) or subretinal space (Wenkel and Streilein, 1998).
ACAID arises because intraocular APCs capture eye-derived antigen,
migrate directly into the bloodstream through the trabecular
meshwork, and trafc to the spleen.
Several lines of evidence support this primary route of migration of eye-derived APCs in ACAID. First, 24e48 h after mice receive
an anterior-chamber injection of antigen, their blood contains APCs
that induce ACAID when injected intravenously into naive mice
(Wilbanks and Streilein, 1991). Second, APCs from the iris and
ciliary body of mice that received an antigen injection in the
anterior chamber induce ACAID when injected intravenously into
naive mice (Wilbanks et al., 1991). Third, conventional APCs treated
in vitro with TGF-b migrate preferentially to the spleen when
injected intravenously into mice (Wilbanks and Streilein, 1992).
Antigen-bearing eye-derived cells (F4/80 positive) come to rest
selectively in the marginal zone of the spleen. Then, CD4 and CD8
T cells that are specic for eye-derived antigen accumulate in the
marginal zone of the spleen. The eye-derived APCs and B cells in the
spleen contribute to the activation of these T cells. Eventually,
antigen-specic Tregs that mediate ACAID emerge from these cell
clusters in the spleen (Niederkorn and Streilein, 1983; Wilbanks
and Streilein, 1990).
17
The CD4 population of Tregs is known as afferent because

these cells suppress the initial activation and differentiation of
naive T cells into Th1-type effector cells. The CD8 population of
Tregs is known as efferent because these cells inhibit Th1mediated immunity, such as delayed-type hypersensitivity. The
CD8 Tregs of ACAID act in the periphery, including the eye,
whereas afferent ACAID CD4 Tregs act in secondary lymphoid
organs (Streilein et al., 2002). Eventually, activated antigen-specic
CD4 and CD8 T cells that differentiate into the antigen-specic
regulatory T cells of ACAID can protect a graft from immune
rejection after transplantation.
Tissue-based ocular mechanisms of immune privilege that
contribute to the ocular defense systems have been identied
(Forrester et al., 2008; Forrester, 2009). An important molecule
contributing to immune privilege in the eye is Fas Ligand (FasL). An
abundance of FasL is constitutively expressed throughout the eye
(Ferguson and Grifth, 2006). FasL induces apoptosis of any activated Fas cells that enter the eye, and FasL-induced cell death can
lead to tolerance and blocks the growth of blood vessels that can
damage the eye (Ferguson and Grifth, 1997; Dick et al., 1999;
Gregory et al., 2002, 2005; Ferguson and Grifth, 2006). TNFrelated apoptosis-inducing ligand is also expressed on ocular
tissues and participates in ocular immune privilege (Ferguson and
Grifth, 2007; Wosik et al., 2007). Additionally, immune regulation provided by ocular resident cells is a critical component of the
ocular defense system.
As described above, ACAID is eye-derived antigen specic
immune regulation. In addition to this, ocular resident cells (PE
cells of iris, ciliary body and retina, CE cells) contribute to the
immune privilege of the eye by another immune regulation which
is not specic to eye-derived antigen. The ocular resident cells are
capable of directly suppressing T cells activated by anti-CD3 antibody, but not by eye-derived antigens. The following chapters
highlight the molecular mechanisms of the immune regulation by
ocular resident cells.
3.1. Ocular resident cells and their direct immune regulation
It is obvious that immune regulation might work much more
efciently at the gate of the bloodeocular barrier rather than after
activated effector CD4 T cells enter the eye. Table 1 summarizes
the immunoregulatory properties of ocular resident cells located at
the inner surface of the bloodeocular barrier. Ocular resident cells,
such as PE cells of the iris, ciliary body, and retina and CE cells, have
immunomodulatory capacity and contribute to ocular immune
privilege (Yoshida et al., 2000; Streilein, 2003; Ishida et al., 2003;
Sugita, 2009; Mochizuki, 2009; Hori et al., 2010). For instance,
murine retinal PE cells suppress Th1 cells (Sugita et al., 2006a),
Th17 cells (Sugita et al., 2011b), CD8 T cells (Sugita et al., 2004,
2008), B cells (Sugita et al., 2010b), and macrophages (Zamiri et al.,
2006), and they upregulate Foxp3 regulatory T cells (Sugita et al.,
2008, 2009a). PE cells of the iris, ciliary body, and retina and CE cells
utilize distinct molecular mechanisms related to their anatomical
locations and microenvironments to mediate immunomodulation.
When ocular PE cells isolated from the iris, ciliary body, or retina
of B57BL/6 mice were co-cultured with bystander T cells in the
presence of anti-CD3 antibody (Sugita and Streilein, 2003), T-cell
activation was signicantly suppressed, indicating that all ocular PE
cells are capable of suppressing the activation of target T cells
(Fig. 7). However, when transwell membranes were inserted
between ocular PE cells and target T cells, the iris PE cells failed to
suppress the activation of target T cells (Fig. 7), indicating that cellto-cell contact is necessary for the suppression of responder T cells
by iris PE cells. In contrast, retinal PE cells suppressed T-cell
proliferation even after transwell membranes were inserted
18
Table 1
Summary of immunosuppressive properties of the ocular resident cells.
Ocular resident cells
Use of cell contact
Secretion of soluble factors
Induction of Treg cells
Candidate molecules
Representative reference
Retinal PE
()
()
() (CD4 & CD8)
Iris PE
()
()
() (CD8)
Ciliary body PE
()
()
()
Cornea endothelium
()
()
() (CD4 & CD8)
TGFb
TSP-1
PD-L1 (B7-H1)
Galectin-1
PEDF
CTLA-2a
Retinoic acid
TGFb
TSP-1
CD86 (B7-2)
TGFb
TSP-1
TGFb
PD-L1 (B7-H1)
GITRL
CTLA-2a
Sugita et al., 2009a

Futagami et al., 2007
Sugita et al., 2009b
Ishida et al., 2003
Zamiri et al., 2006
Sugita et al., 2008
Kawazoe et al., 2012
Sugita et al., 2006b
Sugita and Streilein, 2003
Yamada et al., 2010
Sugita et al., 2009c
Hori et al., 2010
TSP-1, thrombospondin-1; PEDF, pigment epithelial-derived factor; CTLA-2a, cytotoxic T lymphocyte antigen-2 alpha, glucocorticoid-induced tumor necrosis factor receptor
family-related protein ligand (GITRL).
between retinal PE cells and target T cells (Fig. 8), indicating that
the suppressive activity of retinal PE cells is mainly mediated by
soluble factors. Ciliary body PE cells had an intermediate property,
retaining a modest but signicant capacity to suppress T-cell activation across the membrane (Fig. 7). These observations are in
accordance with the disparate microenvironments in which these
ocular PE cells are located. Namely, iris PE cells are located in the
anterior segment of the eye and face the aqueous humor. In such an
environment, soluble factors would be readily diluted by the
aqueous humor, and cell-to-cell contact would be most efcient. On
the other hand, retinal PE cells are located in the cell-rich microenvironment between the choroid and the neural retina. In such
a cell-dense microenvironment, soluble factors would be much
more efcient than cell-to-cell contact.
3.1.1. Direct T-cell suppression by retinal PE cells
To identify soluble factors participating in the immunoregulation by retinal PE cells, we performed a GeneChip microarray assay
with PE cells of the iris, ciliary body, and retina of C57BL/6 mice
(Futagami et al., 2007). Several eye-derived immunoregulatory
genes were expressed at high levels in ocular PE cells. Among
them, two molecules were identied as key soluble factors for
immunoregulation by retinal PE cells, thrombospondin-1 (TSP-1)
and TGF-b.
TGF-b is an intense immunosuppressive factor that is expressed
in ocular PE cells at the gene level and the protein level. A TGFb bioassay using MvILu cells demonstrated that retinal PE cells
produce and secrete a soluble form of TGF-b (Sugita et al., 2006a).
We further investigated whether TGF-b signaling is necessary for
immunosuppression by retinal PE cells by using dominant-negative
TGF-b receptor II (TGF-b RII) transgenic mice, in which TGFb signals do not enter T cells through their TGF-b receptors. The
proliferative response of activated T cells from wild-type mice was
greatly suppressed by retinal PE cells, whereas the activation of T
cells from dominant-negative TGF-bRII mice was enhanced rather
than suppressed by retinal PE cells. Thus, TGF-b signals are essential
Fig. 7. Immunosuppressive properties of murine ocular pigment epithelial cells (iris, ciliary body, retina) on activation of bystander T cells. The gure is reproduced (Sugita and
Streilein, 2003, Fig. 1) with permission. A. Iris pigment epithelial cells (IPE): IPE greatly suppressed activation of bystander T cells, and the suppression completely disappeared
by the use of transwell cell-insert membranes. B. Ciliary doby pigment epithelial cells (CBPE): CBPE also greatly suppressed activation of bystander T cells, and the suppression was
moderately disturbed by the use of transwell cell-insert membranes. C. Retinal pigment epithelial cells (RPE): RPE also greatly suppressed activation of bystander T cells, but the
suppression was minimally affected by the use of transwell cell-insert membranes.
Fig. 8. Experimental procedures to identify induction of regulatory T (Treg) cells by

ocular pigment epithelial cells. The gure is reproduced (Mochizuki, 2009, Fig. 29)
with permission.
for T-cell suppression by retinal PE cells. Under normal conditions,

TGF-b is constitutively expressed on ocular PE cells in a latent form,
which is converted to the active form by TSP-1. TSP-1 is expressed
on all three types of ocular PE cells at the gene level and the protein
level, but its expression level on retinal PE cells is particularly high
(Futagami et al., 2007). The function of TSP-1 was tested by pretreating retinal PE cells with antibodies to various soluble factors.
Only the anti-TSP-1 antibody neutralized the suppressive activity of
retinal PE cells, indicating that TSP-1 is necessary for T-cell
suppression by retinal PE cells. Furthermore, the addition of
recombinant TSP-1 to the culture medium of retinal PE cells
enhanced the secretion of active TGF-b, but not total TGF-b, by
retinal PE cells (Futagami et al., 2007).
Another co-stimulatory factor, programmed cell death ligand
(PD-L1 or B7-H1), is involved in T-cell suppression by retinal PE
cells (Usui et al., 2008; Sugita et al., 2009b). PD-L1 is widely
expressed on the thymus, spleen, heart, endothelium, epithelium,
tumors, and immunocytes such as T cells, B cells, DCs, and monocytes (Dong et al., 1999; Yamazaki et al., 2002). In the eye, PD-L1 is
constitutively expressed on CE cells and provides a negative costimulatory signal for effector T cells that helps to inhibit corneal
allograft rejection (Hori et al., 2006). In addition to CE cells, human
retinal PE cell lines constitutively express PD-L1 co-stimulatory
molecules, and retinal PE cells can suppress programmed cell death
1 (PD-1)-expressing human T cells (Usui et al., 2008). We further
examined whether murine retinal PE cells can suppress the activation of bystander T cells during inammatory conditions (Sugita
et al., 2009b) by using IFNg-pretreated retinal PE cells. Although
primary murine retinal PE cells did not express PD-L1, the expression of PD-L1 was induced on the surface of IFNg-pretreated retinal
PE cells. The IFNg-pretreated retinal PE cells suppressed activation
of PD-1 bystander T cells, but they failed to suppress bystander T
cells from PD-1 KO mice. Anti-PD-L1 antibody neutralized the
suppression of bystander T cells by IFNg-pretreated retinal PE cells.
Thus, PD-L1 molecules are expressed on retinal PE cells in the
presence of inammatory cytokine IFNg, and the interaction
between PD-L1-expressing retinal PE cells and IFNg-producing Th1
cells provides negative co-stimulatory signals, thereby suppressing
bystander Th1-type cells.
Based on these ndings, the following model has been proposed
to explain the molecular mechanisms of direct suppression of
bystander T cells by retinal PE cells. TSP-1 molecules expressed on
retinal PE cells convert latent TGF-b to active TGF-b, and then
soluble TGF-b is secreted from retinal PE cells. The soluble form of
active TGF-b provides negative signals to activated CD4 T cells
through their TGF-b receptors and suppresses the activation of
bystander T cells. The interaction between PD-L1 molecules on
retinal PE cells and PD-1 molecules on IFNg-producing bystander T
cells provides a negative co-stimulatory signal to bystander T cells
under inammatory conditions.
19
3.1.2. Direct T-cell suppression by iris PE cells

To identify unique regulatory molecules on iris PE cells that
participate in immunosuppression via cell-contact-dependent
mechanisms, the gene expression of co-stimulatory molecules
was compared among PE cells of the iris, ciliary body, and retina
(Sugita and Streilein, 2003). Among the tested molecules, only
CD86 (B7-2) molecules were greatly expressed on iris PE cells but
not expressed on retinal PE cells and weakly expressed on ciliary
body PE cells. The expression of B7-2 on iris PE cells was also
demonstrated at the protein level by ow cytometry. B7-2 molecules function as co-stimulatory molecules on antigen-presenting
cells. To investigate the function of B7-2 molecules on iris PE
cells, we used B7-2 KO mice (Sugita et al., 2004). Iris PE cells from
wild-type mice strongly suppressed T-cell activation, while iris PE
cells from B7-2 KO mice failed to suppress T-cell activation, indicating that B7-2 molecules expressed on iris PE cells are essential
for direct bystander T-cell suppression by iris PE cells. Because
cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a ligand
for the B7-2 molecule, we further performed immunohistochemical studies to determine if CTLA-4 molecules were expressed on
activated T cells when T cells were co-cultured with iris PE cells.
CTLA-4 was clearly expressed on the cell surface of anti-CD3stimulated T cells that contacted iris PE cells (Sugita et al., 2004).
Immunohistochemical studies also demonstrated that B7-2 molecules were expressed on the cell surface of iris PE cells that contacted anti-CD3-stimulated T cells. As for the function of CTLA-4,
the activation of bystander T cells from CTLA-4/ wild-type mice
was greatly suppressed by iris PE cells, while T cells from CTLA-4/
KO mice were not suppressed by iris PE cells, indicating that the
interaction between B7-2 (CD86) molecules and CTLA-4 molecules
plays a key role in the direct immunosuppressive activity of iris PE
cells on activated T cells.
Although B7-2 molecules and CTLA-4 molecules play a key role
in the immunosuppressive activity of iris PE cells, these molecules
are co-stimulatory molecules, not primary immunosuppressive
molecules. Like the posterior segment of the eye, the key immunosuppressive factor in the anterior segment is TGF-b. TGF-b is
expressed on ocular PE cells of the iris, ciliary body, and retina.
Ocular tissues (iris, ciliary body, and retina) express TGF-b at the
mRNA level and the protein level (Sugita et al., 2006b). In addition,
cultured iris PE cells were positively stained with anti-TGF-b2
antibody (cell surface and intracellular). The function of TGF-b was
investigated by using transgenic dominant-negative TGF-b RII
mice, in which TGF-b signals do not enter T cells through T-cell
receptors (Sugita et al., 2006b). The activation of bystander T cells
from dominant-negative TGF-b RII mice was not suppressed by iris
PE cells while that from wild-type mice was greatly suppressed by
iris PE cells, indicating that TGF-b signals from iris PE cells to
bystander T cells are essential.
3.1.3. Direct T-cell suppression by CE cells
CE cells are in contact with the aqueous humor as a part of the
inner surface of the anterior segment of the eye, like iris PE cells.
Because human CE cells lack regenerative capacities, they have
unique mechanisms that provide protection from immunemediated cell damage. Human CE cells inhibit IL-2 production by
T cells (Kawashima et al., 1994) and constitutively express CD95
ligand (Fas L), which induces the apoptosis of T cells expressing CD
95 (Fas) molecules (Grifth et al., 1995; Yamagami et al., 1997).
Another immune mechanism, the interaction between costimulatory molecules PD-L1 and PD-1, was more recently discovered. Hori et al. (2006) demonstrated that PD-L1 co-stimulatory
molecules expressed on CE cells provide negative co-stimulation
for effecter T cells to inhibit corneal allograft rejection. We
20
Fig. 10. Molecular mechanisms of regulatory T (Treg) cells by iris pigment epithelial
cells. PE: pigment epithelial cells, TCR: T cell receptor, CTLA: cytotoxic T lymphocyteassociated antigen, TSP: thrombospondin, mTGFb: membrane bound transforming
growth factor b, TGFbR: transforming growth factor b receptor.
Fig. 9. Induction of regulatory T cells by murine ocular pigment epithelial cells. The
gure is reproduced (Sugita et al., 2008, Fig. 1) with permission.
hypothesized that this mechanism to might also protect CE cells

from activated effector T cells inltrating the anterior segment of
the eye with uveitis. To examine this hypothesis, we studied the
suppressive activity of CE cell lines from human primary CE cells
and allogeneic activated T cells or T-cell clones established from
inltrating cells in the eyes of uveitis patients as target cells (Sugita
et al., 2009c). Human CE cells suppressed both in vitro proliferation
and IFNg production by activated allogeneic CD4 T cells and T-cell
clones from uveitis patients via a cell contact-dependent mechanism, like iris PE cells. Human CE cells constitutively expressed costimulatory PD-L1 and PD-L2 molecules, and their expression was
enhanced by IFNg. Human CE cells efciently inhibited the proliferation of PD-1 Th1 cells and activated CD4 T cell lines and clones
established from patients with ocular inammatory diseases such
as Behets disease, sarcoidosis, VKH disease, and corneal endotheliitis. A neutralizing antibody for PD-L1, but not PD-L2, blocked
the suppressive effect of human CE cells on Th1 cells (Sugita et al.,
2009c). Thus, CE cells suppress Th1-inltrating effector CD4 T cells
by a cell-contact mechanism via the PD-L1/PD-1 interaction and
participate in the immune system in the anterior segment of the
eye.
cell generation by ocular resident cells, we can identify candidate

cells and molecules for new immunotherapies to treat ocular
inammatory diseases.
We performed an in vitro study to determine if ocular resident
cells can generate Treg cells from activated T cells as follows (Sugita
et al., 2006c) (Fig. 8). Naive T cells (CD4 or CD8) were isolated
from C57BL/6 mice and cultured with PE cells of the iris, ciliary
body, and retina in the presence of a low concentration of anti-CD3
antibody (0.01 mg/mL). The T cells exposed to ocular PE cells were
harvested, gamma-irradiated, and added to responder CD3 T cells
that were harvested from C57BL/6 mice. The responder T cells and
ocular PE cell-exposed T cells were co-cultured in the presence of
anti-CD3 antibody (1.0 mg/mL), and then the proliferation and
cytokine production by responder T cells were assessed. The
suppression of responder T cells would indicate that the ocular PE
cells generated Treg cells. As described below, the mode of action
and molecular mechanisms of Treg-cell generation by ocular resident cells differ depending on the microenvironment of the ocular
resident cells.
3.2. Regulatory T cells generated by ocular resident cells

In addition to direct immune suppression, ocular resident cells
(iris PE cells, ciliary body PE cells, retinal PE cells, and CE cells) can
induce the conversion of activated T cells to regulatory T (Treg)
cells. Ocular resident cell-induced Treg cells can greatly suppress
the activation of T cells, thereby down-regulating the immune and
inammatory responses in the eye and maintaining ocular
homeostasis. By understanding the molecular mechanisms of Treg-
Fig. 11. Molecular mechanisms of regulatory T (Treg) cells by retinal pigment epithelial
cells. PE: pigment epithelial cells, TCR: T cell receptor, CTLA: cytotoxic T lymphocyteassociated antigen, TSP: thrombospondin, sTGFb: soluble transforming growth factor
b, TGFbR: transforming growth factor b receptor, CathL: cathepsin L.
Fig. 12. Molecular mechanisms of regulatory T (Treg) cells by corneal endothelial cells.
CE: corneal endothelial cells, TCR: T cell receptor, CTLA: cytotoxic T lymphocyteassociated antigen, TSP: thrombospondin, mTGFb: membrane bound transforming
growth factor b, TGFbR: transforming growth factor b receptor, CathL: cathepsin L.
3.2.1. Regulatory T cells generated by ocular PE cells

Ocular PE cells from the iris and retina are able to generate Treg
cells (Fig. 9) (Sugita et al., 2008), but the mode of action and
molecular mechanisms of these two types of ocular PE cells are
different. Our studies have revealed the molecular mechanisms
responsible for the generation of Treg cells by iris PE cells (Fig. 10)
(Sugita et al., 2006b, 2006c; 2007, 2008; 2010a). Iris PE cells
primarily convert CD8 T cells, but not CD4 T cells, into Treg cells.
Iris PE cells provide negative signals to generate CD8 T cells via
cell-contact-dependent mechanisms, including interactions
between costimulatory B7-2 (CD86) molecules on iris PE cells and
CTLA-4 on CD8 T cells. TSP-1 expressed on iris PE cells converts
latent TGF-b to the active membrane-bound form. The binding of
active TGF-b to its receptors on CD8 T cells signals these cells to
21
convert into Treg cells. The iris PE cell-exposed CD8 T cells, which
express CD25 and Foxp3, suppress the proliferation of activated
responder T cells and produce suppressive cytokines such as IL-10
and TGF-b. The iris PE cell-exposed CD8 T cells express high
levels of co-stimulatory PD-L1 molecules on their cell surface and
suppress the activation of IFNg-producing Th1 cells that express
PD-1, indicating that negative PD-L1 signals are also required for
the induction of Treg cells by iris PE cells. Thus, iris PE cells have the
capacity to convert CD8 T cells, but not CD4 T cells, into
CD25Foxp3 Treg cells that suppress the proliferation of activated
T cells and produce suppressive cytokines.
Unlike iris PE cells, retinal PE cells convert both CD4 T cells and
CD8 T cells into Treg cells, but the conversion occurs more
frequently in CD4 T cells than in CD8 T cells (Sugita et al., 2008).
In addition, retinal PE cells use soluble factors, but not cell-contact
mechanisms, to generate Treg cells. Our studies have revealed the
molecular mechanisms of Treg induction by retinal PE cells (Fig. 11)
(Sugita et al., 2008, 2009a, 2009b; Sugita, 2009). The proliferation
of CD4 responder T cells was greatly suppressed by retinal PE cellexposed CD4 T cells, while the proliferation of CD8 responder T
cells was weakly but signicantly suppressed by retinal PE cellexposed CD8 T cells. The induction of Treg cells by retinal PE
cells was not inuenced by a cell-culture insert membrane when
retinal PE cells and responder T cells were co-cultured, indicating
that the generation of Treg cells by retinal PE cells is mediated by
soluble factors. Signaling for Treg generation is provided by interactions between TGF-b receptors on CD4 T cells and soluble TGFb secreted by retinal PE cells. GeneChip analysis of iris, ciliary body,
and retinal PE cells revealed that CTLA-2a, a cysteine protease
inhibitor (cathepsin L inhibitor), is a unique molecule that is
constitutively expressed on retinal PE cells but not on iris or ciliary
body PE cells (Sugita et al., 2008). Recombinant CTLA-2a suppressed the proliferation of responder T cells, and siRNA CTLA-2a
blocked the ability of retinal PE cells to generate Treg cells (Sugita
Fig. 13. Capacity of retinal pigment epithelial cells (RPE) to convert T cells into regulators. The gure and legends are reproduced (Horie et al., 2010, Fig. 1) with permission. (A)
Puried human CD4 T cells were cultured with supernatants from human RPE cells (ARPE-19) for 24 h in the presence of anti-CD3 antibody (0.1 mg/mL), harvested, X-irradiated,
and used as Treg cells (RPE-induced T reg cells: black bar). The human RPE-induced Treg cells were added to cultures containing naive responder T cells (T resp, open bar) plus antiCD3. (B) Puried murine CD4 T cells from a spleen were cultured with supernatants of primary cultured RPE cells for 24 h in the presence of anti-mouse CD3 antibody, harvested,
X-irradiated, and used as Treg cells. The murine RPE-induced Treg cells were added to cultures containing target responder T cells.
22
et al., 2008), indicating that CTLA-2a is an important soluble factor

of retinal PE cells for the generation of Treg cells.
Recently, we showed that retinal PE cells produce retinoic acid,
thereby enabling bystander T cells to be converted into Treg cells
through the production of TGF-b, a candidate immunosuppressive
molecule for Treg induction (Kawazoe et al., 2012). Indeed, the
conversion of T cells into Treg cells in the eye requires retinoic acid
(Zhou et al., 2012). Similar to iris PE cell-induced Treg cells, retinal
PE-induced Treg cells also express CD25high and Foxp3 (Fig. 11).
3.2.2. Regulatory T cells generated by CE cells
We have studied the capacity of human and murine CE cell lines
to generate Treg cells and determined the corresponding molecular
mechanisms (Fig. 12) (Sugita et al., 2009c, 2011a; Yamada et al.,
2010). Cultured human CE cells produce membrane-bound active
TGFb2 that is essential to suppress CD8 T-cell activation via direct
cell contact. Human CE cells also express co-stimulatory molecules
such as PD-L1 and PD-L2 and secrete TSP-1, but only membranebound TGFb2 is actually delivered to the CD8 T cells. Treg generation by human CE cells was signicantly abolished by a cellculture insert membrane, indicating that the conversion of CD8
T cells into Treg cells requires cell-to-cell contact. Anti-TGFb2 or

TGFb2 siRNA blocked the ability of human CE cells to generate Treg
cells, indicating that Treg generation is mediated by membranebound TGFb2. The phenotype of human CE-generated Treg cells is
CD25high and Foxp3, and these cells produce soluble forms of
TGFb1 but not TGFb2.
Like human CE cells, murine CE cells can induce Treg cells
(Sugita et al., 2011a). Murine CE cells can convert both CD4 T cells
and CD8 T cells into Treg cells in vitro. CE-exposed CD4 T cells
express CD25 and intracellular Foxp3. Depletion of the CD25 cell
population from murine CE-exposed CD4 T cells blocked the
suppression of responder T cells. In the presence of a transwell
membrane, murine CE-exposed CD4 T cells did not express Foxp3
and failed to suppress responder T cells, indicating that direct cell
contact is necessary for the induction of Treg cells. Both human and
murine CE cells express TGF-b, which is important for the induction
of Treg cells. In addition, murine CE cells express CTLA-2a,
a cysteine proteinase inhibitor, on their cell surface. Overexpression of CTLA-2a on murine CE cells promotes TGF-b expression. CE-exposed Treg cells failed to suppress responder T cells
when the murine CE cells were pretreated with CTLA-2a siRNA or
Fig. 14. Capacity of RPE-induced Treg cells to suppress intraocular T cells. The gure is reproduced with permission (Horie et al., 2010, Fig. 5). Human RPE (ARPE-19) were pretreated
with recombinant TGFb2, and the supernatant of TGFb-pretreated RPE was harvested. Puried human CD4 T cells were cultured with the supernatants from TGFb-pretreated RPE
cells, X-irradiated, and used as RPE-induced human Treg cells. Target T-cell clones were established from inltrating cells in the aqueous humor of patients with active uveitis:
sarcoidosis, VogteKoyanagieHarada disease, acute anterior uveitis, Behet disease, acute retinal necrosis and cytomegalovirus retinitis.
antibody to CTLA-2a, indicating that murine CE cells produce CTLA2a on their surface, thereby converting bystander CD4 T cells into
Treg cells by TGF-b promotion.
Our studies have shown that ocular resident cells have the
potential to inhibit T-cell activation and promote Treg-cell generation. Ocular Treg conversion in vivo was conrmed by Caspi and
colleagues for the rst time (Zhou et al., 2012). They also showed
that the recognition of retinal Ag is required for Treg conversion
and that retinoic acid is critical for the conversion as there is
a limited amount of TGF-b in the eye. Treg conversion is impaired
under inammatory conditions. Primed and non-converted T cells
do not express effector functions in the eye. The contribution of
ocular resident cells to the phenomenon in the eye needs to be
elucidated to gain a more detailed understanding of tissue-based
mechanisms in ocular defense.
3.2.3. Regulatory T cells in humans
Our discussion of immune regulation by the direct immunosuppressive effects of ocular resident cells and their capacity to
generate Treg cells is based on studies performed with murine cells.
It is important to determine if human ocular resident cells also have
the capacity to convert bystander T cells into Treg cells. For this
purpose, we determined if human retinal PE cells, ARPE-19 cells,
could generate Treg cells in vitro (Horie et al., 2010). After incubation with anti-CD3 antibody, puried CD4 T cells exposed to
supernatants of human retinal PE cells (ARPE-19 cells) were harvested, X-irradiated, and added to secondary cultures containing
target responder T cells, which were established from allogeneic T
cells from the peripheral blood mononuclear cells of healthy
volunteers. Unlike the corresponding studies with murine cells,
human CD4 T cells exposed to supernatants of human retinal PE
cells did not suppress the activation of responder T cells (Fig. 13)
(Horie et al., 2010). When retinal PE cells are treated with
recombinant TGFb in vitro, their production of immunosuppressive
factors such as TGFb and TSP-1 is greatly upregulated (Futagami
et al., 2007). Therefore, we pretreated ARPE-19 cells with
recombinant human TGFb2 (Horie et al., 2010). The TGFb2pretreated human retinal PE cells produced large amounts of
immunosuppressive factors (TGFb1, TGFb2, TSP-1, and PGE2) and
secreted them into the supernatant. Furthermore, we conrmed
that CD4 T cells exposed to supernatants from rTGFb2-pretreated
retinal PE cells secreted signicant amounts of the active form of
TGFb1, IL-10, or IFNg. The CD4 T cells exposed to supernatants
from rTGFb2-pretreated retinal PE cells suppressed the activation
of pan T cells, B cells, CD4 T cells, and Th1 cells in vitro. More
importantly, the CD4 T cells exposed to supernatants from human
rTGFb2-pretreated retinal PE cells (RPE-induced human Treg cells)
functionally suppressed the activation of CD4 T-cell clones
established from the ocular inltrating cells of patients with ocular
inammatory diseases (sarcoidosis, VKH disease, Behets disease,
acute anterior uveitis, acute retinal necrosis, and cytomegalovirus
retinitis) (Fig. 14) (Horie et al., 2010). Thus, RPE-induced human
Treg cells can suppress activated T cells in the eyes of patients with
autoimmune uveitis as well as infectious uveitis. This capacity of
RPE-induced human Treg cells was completely blocked by pretreating retinal PE cells with TGFb siRNA or anti-TGFb antibody. The
RPE-induced human Treg cells expressed Foxp3, CD25, and CD152
(CTLA-4), and the CD4CD25 Treg cells greatly suppressed
responder bystander T cells, whereas CD4CD25 Treg cells did not.
These in vitro assays indicate that supernatants of TGFb-exposed
human retinal PE cells can convert CD4 T cells into Treg cells,
thereby suppressing T-cell activation.
The current investigations imply the possibility of using Treg
cells established from humans for the treatment of intraocular
inammatory diseases with non-infectious etiology. However, the
23
safety and efcacy of human Treg cells in human diseases must rst
be comprehensively studied.
4. Conclusion
Uveitis is a sight-threatening disease caused by autoimmune or
infection-related immune responses. Studies of EAU and human
diseases such as VogteKoyanagieHarada disease and HTLV-1
uveitis imply that activated CD4 T cells, Th1 and Th17 cells, play
an effector role in ocular inammation. The eye has a unique
regional immune system that protects vision-related cells and
tissues from these effector T cells. The immunological balance
between the pathogenic CD4 T cells and regional immune system
in the eye helps to maintain ocular homeostasis and good vision.
Ocular resident cells at the inner surface of the oculareblood
barrier (CE cells, iris PE cells, ciliary body PE cells, and retinal PE
cells) contribute to the regional immune system of the eye. Murine
ocular resident cells directly suppress the activation of bystander T
cells and the production of inammatory cytokines. The ocular
resident cells possess distinct properties of immunoregulation that
are related to disparate anatomical locations. CE cells and iris PE
cells, which are located at the anterior segment of the eye and face
the aqueous humor, suppress T-cell activation via cell-to-cell
contact mechanisms, whereas retinal PE cells suppress T-cells
activation via soluble factors. In addition to direct immune
suppression, the ocular resident cells have another unique immunosuppressive property, the induction of CD25Foxp3 Treg cells
that suppress the activation of bystander T cells. Iris PE cells convert
CD8 T cells into Treg cells, while retinal PE cells convert CD4 T
cells and, to a lesser extent, CD8 T cells into Treg cells. CE cells
convert both CD4 T cells and CD8 T cells into Treg cells. Immunomodulation by ocular resident cells is mediated by soluble or
membrane-bound molecules including TGFb, TSP-1, B7-2 (CD86),
CTLA-2a, PD-L1 (B7-H1), galectin 1, pigment epithelial-derived
factor, GITRL (glucocorticoid-induced tumor necrosis factor
receptor family-related protein ligand), and retinoic acid (Table 1).
The Treg-cell induction properties of human and murine retinal PE
cells are similar. Although safety and efcacy must be addressed, it
appears that human Treg cells induced by ocular resident cells such
as retinal PE cells and related immunosuppressive molecules are
promising for application in immune therapy for refractive autoimmune uveitis in humans.
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Progress in Retinal and Eye Research 33 (2013) 10e27

Contents lists available at SciVerse ScienceDirect

Progress in Retinal and Eye Research

Immunological homeostasis of the eye

Uveitis is a sight-threatening disease caused by autoimmune or infection-related immune responses.

* Corresponding author. Tel.: 81 3 5803 5296; fax: 81 3 5803 0145.

M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27

2. T cells and intraocular inammation

2.1. Experimental autoimmune uveoretinitis

M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27

autoimmune regulator AIRE, which is responsible for the ectopic

self-specic cells circulate without activation under healthy

M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27

2001). Immature DCs have the potential to expand nTreg cells in

lymph node down-regulates pathogenic cells and suppresses

M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27

until Yamaki et al. (2000a, 2000b) established an animal model of

uveitis 2 weeks after immunization, followed by depigmentation in

M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27

To determine if ocular inltrating lymphocytes are sensitized to the

Fig. 4. Hypothesis of molecular mechanisms of VogteKoyanagieHarada disease. The

infection, HTLV-1 uveitis. HTLV-1 is a human retrovirus, an RNA

Fig. 5. Seroepidemiology of HTLV-1 in an endemic area. The gure is reproduced

M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27

immunouorescence methods (Sagawa et al., 1995). The provirus

M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27

The CD4 population of Tregs is known as afferent because

M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27

Use of cell contact

Secretion of soluble factors

Induction of Treg cells

() (CD4 & CD8)

() (CD4 & CD8)

Sugita et al., 2009a

M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27

Fig. 8. Experimental procedures to identify induction of regulatory T (Treg) cells by

for T-cell suppression by retinal PE cells. Under normal conditions,

3.1.2. Direct T-cell suppression by iris PE cells

M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27

hypothesized that this mechanism to might also protect CE cells

cell generation by ocular resident cells, we can identify candidate

3.2. Regulatory T cells generated by ocular resident cells

M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27

3.2.1. Regulatory T cells generated by ocular PE cells

M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27

et al., 2008), indicating that CTLA-2a is an important soluble factor

T cells into Treg cells requires cell-to-cell contact. Anti-TGFb2 or

M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27

M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27

M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27

M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27

M. Mochizuki et al. / Progress in Retinal and Eye Research 33 (2013) 10e27

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