Originally published online as doi:10.1189/jlb.0606383 on December 28, 2006
Published online before print December 28, 2006
(Journal of Leukocyte Biology. 2007;81:593-598.)
© 2007
by Society for Leukocyte Biology
An eye’s view of T regulatory cells
Joan Stein-Streilein1 and
Andrew W. Taylor
Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
1 Correspondence: Schepens Eye Research Institute, 20 Staniford Street, Boston, MA 02114, USA. E-mail: joan.stein{at}schepens.harvard.edu
 |
ABSTRACT
|
|---|
T regulatory (Treg) cells have been studied for more than 30 years. Recently, changing technology and attitudes have led to new interest in T cell regulation of the immune responses. The eye is an immune-privileged site with unique mechanisms for the prevention of damaging immune inflammation. The eye fashions its Treg cells in novel ways to prevent immune inflammation locally and systemically. The purpose of this mini-review is to condense and summarize reports of Treg cells dependent on the eye in the context of the Treg literature in general.
Key Words: immune regulation • TGF-ß • ACAID
|
INTRODUCTION
|
|---|
At the bases of immune regulation are the concepts of self and nonself. In mouse and humans, there are two principally different mechanisms that allow for self-tolerance: Central tolerance involves thymic-negative selection, and peripheral tolerance induces specialized T cells with regulatory capacities extrathymically. In central tolerance, self-reactive T cells are deleted and appear to be most relevant and effective for tissue-specific antigens [1
]. However, even if the thymus is working, autoreactive T cells may escape into the blood circulation and seed peripheral lymphoid organs. Moreover, not all individuals with autoreactive T cells have autoimmune diseases, as an entire system of T regulatory (Treg) cells responds accordingly to maintain a lack of autoreactivity. Tissue-specific autoimmunity can be inhibited by subpopulations of CD4+ cells [2
, 3
], and recent studies show that suppressive CD8+ cells can be protective against autoimmune disease [4
, 5
].
|
TREG CELLS
|
|---|
Suppressor T cells were first studied in the 1970s for their ability to exert feedback inhibition of in vivo immune responses [6
, 7
]. At least one population of cells at that time was identified as Ly1+ Qa-1+ [7
]. Modern immunology now recognizes that Treg cells play a central role in controlling the immune activity against self-antigens [8
]. Moreover, there appear to be distinct phenotypes of regulatory cells, which include CD4+, CD8+, and in some instances, CD1d-restricted cells known as NKT cells [2
, 9
10
11
12
13
14
15
].
|
CD4+ TREGs
|
|---|
Although T cells that regulate the immune response may be CD4+ or CD8+, the most frequently studied Treg cells are CD4+ CD25+ cells, which arise naturally within the thymus [16
]. The population of CD4+ Tregs, that express the high-affinity IL-2 receptor (IL-2R), makes up 5–10% of the lymphocyte population in mice and men [17
]. Also, in common amongst the Treg cells is the expression of the forkhead/winged-helix transcription factor family, forkhead box protein 3 (Foxp3) [18
, 19
]. These cells include a population of cells that express (although not exclusively) CD45RBlo, CD5, OX40, 4-1BB, CTLA-4, and glucocorticoid-induced TNFR surface markers. A subpopulation may express CD103 (human mucosa lymphocyte antigen) [20
, 21
]. However, as more studies are performed, it seems that these markers are found on a variety of lymphocyte subpopulations. Although Tregs are generated in the thymus and the periphery, the CD25+ surface phenotype is a characteristic of thymic Tregs, and in the periphery, CD25+ and CD25– CD4+ populations may have regulatory function [22
].
Conflicting results are published about the inhibitory cytokines that may be involved in Treg-mediated suppression of T cell targets. Moreover, it is not clear if the T cell is the target or if the APC is critically suppressed. The two major cytokines involved in Treg-mediated suppression are IL-10 and TGF-ß, that is a pleiotropic cytokine that regulates inflammation, induction of self-tolerance, oral tolerance, ocular tolerance, and autoimmunity and is thought to mediate Treg function. Tregs are known to produce high levels of TGF-ß1 in secreted and membrane-bound forms. There are conflicting reports about whether TGF-ß is critical for Treg cell suppression in other T cells. TGF-ß may mediate suppression or render target T cells more susceptible to Treg-dependent suppression. TGF-ß may also induce Tregs directly through the induction of Foxp3 and/or Treg proliferation. Flavel and colleagues [23
] showed that the TGF-ß-dependent generation of a high frequency of Tregs in islet cells reflects in situ expansion. Just as Tregs may suppress via TGF-ß-dependent or independent mechanisms, TGF-ß itself may regulate immune response via Treg-dependent and -independent mechanisms. IL-10 has also been implicated as a mediator of suppression, but its role is variable depending on that model [24
25
26
].
In addition, a mechanism of cell contact-dependent suppression by the Treg may involve the expression of B7 molecules (CD80 CD86) on their cell surface, engaging CTLA-4 on the surface of activated effector T cells. It is important that in contrast to activating signals by B7 engagement of CD28, the B7 ligation of CTLA-4 is inhibitory. Thus, it is not unexpected that the ligation transmits suppressive signals to the APC by its engagement of CTLA-4 [27
].
|
CD8+ AND OTHER TREG CELLS [8 , 28 29 30 ]
|
|---|
There are Treg subsets described, which are outside of the CD4+ compartment. CD8+ Tregs are generated through oral exposure to alloantigen and after antigen delivery to the anterior chamber in the eye [31
, 32
]. Seino and colleagues [33
] showed that NKT cells may be directly suppressive, but Sonoda et al. [34
] found that the NKT cell is not directly suppressive but contributes to the environment for the generation of CD8+ Treg cells. Others report that double-negative T cells contribute to the elimination of CD8+ T-reactive cells to regulate immune responses [35
]. With this short background and the many reviews available about the topic of Treg cells [17
, 29
, 36
, 37
], our goal here is to review what is known about the Treg cells that are involved in maintaining the immune-privileged sites.
|
IMMUNE PRIVILEGE
|
|---|
The immune response is designed to protect the body from danger, infection, and malignant cells [38
]. During the early years of immunology, much was learned about the immune process by investigators in the field of transplantation. Medawar [39
, 40
] coined the term immune-privileged for organs and tissues that accepted foreign grafts for an extended period of time. As the study of immunology exploded in the 1960s and 1970s, models of immune privilege were developed. Amongst the most-studied models of immune privilege is the model of peripheral tolerance induction in the eye, called anterior chamber-associated immune deviation (ACAID) [41
]. Other immune-privileged sites are the female reproductive tract [42
], testis [43
44
45
], and the brain [46
47
48
]. Some of the mechanisms shown to function for tolerance induction in the eye have been shown to be true for other immune-privileged sites as well [43
, 47
]. The immune response to eye-inoculated or tissue antigens is an active immune response that induces a Treg cell to suppress Th1 and Th2 effector cells [49
, 50
]. Thus, the divergence from the expected immune response appears to be along two lines of immune cellular behavior, as it includes immune defense without inflammation and a strong Treg cell response to control the responses that do occur.
Early studies by Wilbanks and Streilein [51
] reported that an afferent CD4+ Treg and efferent CD8+ Treg developed in response to antigen inoculated in the anterior chamber [41
]. Both of these Treg cell responses are expressed in the periphery and although never tested are presumed to function in the local eye environment. As the assay used to test for suppression involves the suppression of the effector T cell response or delayed-type hypersensitivity (DTH) responses in vivo, most of the information generated about Tregs in ACAID relates to the efferent CD8+ Treg cell. However, Keino et al. [52
, 53
] recently reported new insights into the afferent CD4+ Treg and the efferent CD8+ Treg cells using transgenic T cell in vitro ACAID assays.
The cell that is central to the development of the CD4+ and CD8+ Treg in ACAID is the F4/80+ APC, which leaves the eye and transports the antigen to the marginal zone (MZ) of the spleen. The putative eye-derived APC secretes chemokines (MIP-2) along the way, which recruit a CD4+ invariant (i)NKT cell to the zone to [54
, 55
] interact with CD1d+ MZ B cells [56
] and T cells. The F4/80 protein is required for the successful interaction of the cell aggregates to generate the efferent CD8+ Treg, as F4/80 null mice are unable to suppress DTH to OVA following anterior chamber (a.c.) injection of OVA [57
]. The requirement for F4/80 protein expression is also relevant for the generation of the CD8+ Treg cell in low-dose oral tolerance, another peripheral tolerance model that requires iNKT cells [57
, 58
]. It is interesting that the ACAID efferent CD8+ Treg cell does not require a traditional CD4+ T cell for its development, as CD8+ Tregs can be generated in Class II knockout (KO) mice following antigen inoculation into the a.c. [59
]. The iNKT cell required for ACAID induction expresses CD4, as removal of the NKT cell with antibodies to CD4 abrogates the ability of the Class II KO mice to respond to the a.c. inoculation with the development of CD8+ Treg and the suppression of DTH in local adoptive transfer assays [59
].
Little is known about how the efferent CD8+ Treg cell interferes with T cell effector responses. Unlike the naturally occurring CD4+ CD25+ Treg cells, which can be harvested from naïve mice and make up 5–10% of the lymphocyte population in the spleen, the antigen-specific CD8+ Tregs in the mice with ACAID are far less. Thus, Keino and colleagues [53
] used T cells from OTI transgenic mice [mice express ovalbumen (OVA) T cell receptor (TCR) transgene for OVA presented in the context of Kb] and generated CD8+ Treg by exposing them to tolerogenic APC. After 72 h, newly expressed genes in the CD8+ Treg cells were grouped as genes related to synthesis, secretion, activation, and receptor binding of TGF-ß; genes associated with inhibition or loss of NK or CD8+ T effector function; genes that promote preferential localization to nonlymphoid sites or antigen deposition; and genes associated with a resistance to TCR ligation-induced apoptosis. It is interesting that the antigen-specific, efferent CD8+ Treg cells expressed CD103. Moreover, CD103 protein was involved in their regulatory function, as CD103 null mice did not develop ACAID [53
]. There are at least two ways in which CD103 interactions with its E-cadherin ligand could lead to the development of Treg cells. ACAID-mediating APC up-regulate their expression of E-cadherin [53
]; thus, the CD103 expressed by APC may facilitate interaction with specific T cells [60
, 61
]. Another possibility is that CD103 interactions with E-cadherin may be important for the Treg cell’s activity with vascular endothelial cells [62
].
|
CYTOKINES INVOLVED IN ACAID
|
|---|
TGF-ß2 is known to be a crucial immunomodulatory factor within the eye [63
64
65
]. However, the distinction between TGF-ß2 and TGF-ß1 becomes blurred, as bone marrow cells that are exposed to TGF-ß2 produce TGF-ß1. TGF-ß is a pleiotropic cytokine/growth factor that also has the capacity to suppress aspects of immunity [66
67
68
]. Besides TGF-ß2, there are other major factors found in the eye that can influence the behavior of T cells directly [69
] (Fig. 1
). The presence of such factors was first demonstrated by the ability of healthy, aqueous humor to suppress IFN-
production by Th1 cells [68
, 70
].
These aqueous humor-treated T cells are suppressed in IFN-, IL-4, and IL-10 production but produce TGF-ß1 and proliferate [69
]. The aqueous humor-treated Th1 cells can no longer mediate DTH, even when they are transferred with antigen-pulsed APC into conventional immune tissues. However, the aqueous humor-treated T cells were able to suppress DTH and cytokine production by other Th1 cells [71
]. Aqueous humor-induced Treg cells suppress other T cells through nonspecific mechanisms but require restimulation by their specific antigen to activate the suppressive activity [71
]. These findings demonstrate that the ocular microenvironment constitutively produces potent factors that not only suppress the expression of immunogenic inflammation, but also can manipulate the immune system to respond in a manner that can be described as peripheral immune tolerance. Of the factors found in aqueous humor, it is the neuropeptide 
-MSH that induces Treg cells [69
]. When -MSH is neutralized in whole aqueous humor, so is aqueous humor’s ability to suppress IFN- production by the antigen-stimulated, primed T cells [72
].
The neuropeptide -MSH is a 13-amino acid-long (1.6 kDa), proteolytic cleavage product of pro-opiomelanocortin hormone [73
, 74
]. -MSH suppresses activated macrophage generation of reactive oxygen intermediates, NO, and production of inflammatory cytokines, and -MSH treatment of macrophages induces IL-10 production and enhances expression of -MSH receptors (melanocortin receptors) [75
76
77
]. In mammals, healthy aqueous humor constitutively contains, on average, 20 pM -MSH [72
]. At its ocular, physiological concentration (20 pM), -MSH suppresses antigen-stimulated, primed T cell production of IFN- production with no affect on proliferation [78
].
Similar to aqueous humor-treated, -MSH-treated, primed T cells, activated through their T cell receptor, produce a cytokine profile that lacks IFN-, IL-4, and IL-10 but contains TGF-ß1 [79
]. These T cells, when added to cultures of activated Th1 cells, suppressed Th1 cell production of IFN-. Moreover, if the -MSH-induced Treg cells are generated to a specific autoantigen, they can be adoptively transferred to suppress an autoimmune disease mediated by the autoantigen or by other autoantigens expressed in the involved tissue [79
]. Induction of Treg cells by -MSH is blocked when antibodies against the melanocortin 5 receptor (MC5r) are used [79
]. The -MSH-induced Treg cells are CD25+ CD4+ T cells.
Rodent models of human autoimmune uveoretinitis recover without spontaneous recurrence and differs from uveitis in some humans. This raises the possibility that this aspect of immune privilege in the rodent eye can be initiated during autoimmune uveoretinitis and result in regulation of the autoimmune response. Recently, it was reported that the eye may be a site of CD25+ CD4+ Treg cell induction during the development of experimental autoimmune uveoretinitis (EAU) [80
]. A T cell-mediated immune response in the eye to an antigen expressed in the eye is part of the EAU mechanism. When spleen cells from EAU mice were adoptively transferred into other mice immunized for EAU, the EAU response was suppressed. However, if the eyes of the EAU mice were enucleated before ocular autoantigens are injected, the regulation could not be transferred. It is interesting that CD25+ CD4+ T cells, but not CD8+ T cells, transferred the suppression of EAU [80
]. Post-EAU APC cell populations alone could not transfer regulation [81
]. The post-EAU Treg cells were dependent on -MSH binding to its -MSH receptor (MC5r) within the ocular microenvironment, as spleens from MC5r KO mice with EAU did not transfer suppression [78
]. Although the recovery of the ocular microenvironment from EAU was not dependent on the induction of the MC5r-dependent, regulatory immunity in the spleen, the -MSH-dependent CD25+ CD4+ Treg cell subsequently prevented the expression of a memory immune response to autoantigen [78
]. This finding of ocular autoantigen-specific Treg cells in the post-EAU spleen indicates that there is an intrinsic mechanism in the ocular microenvironment able to control immunity to newly revealed retinal autoantigens [80
]. Amongst the immunosuppressive factors (TGF-ß2, VIP, somatostatin, -MSH) in the ocular microenvironment, -MSH appears to be the most potent anti-inflammatory neuropeptides that in addition to its anti-inflammatory activity, is able to induce the activation of CD25+ CD4+ Treg cells capable of mediating peripheral immune tolerance.
|
CONTACT-MEDIATED SUPPRESSION BY OCULAR PARENCHYMAL CELLS
|
|---|
Immune privilege is achieved within the eye through at least two overlapping and related mechanisms: soluble immunosuppressive and anti-inflammatory factors within the microenvironment (TGF-ß2 and neuropeptides) [64
] and surface molecules expressed on ocular parenchymal cells, especially the pigment epithelium [82
83
84
85
], the corneal epithelium [86
], and the corneal endothelium [87
]. Pigment epithelium of the eye lines the posterior surface of the iris, the ciliary body, and neural retina and thus, partially surrounds the privileged sites [41
] of the anterior chamber [31
], the vitreous cavity [88
], and the subretinal space [89
, 90
], respectively. Cultured and freshly prepared pigment epithelial (PE) cells from iris, ciliary body, and retina are capable of suppressing TCR-dependent activation and promote the generation of Treg cells [84
] of naïve and primed T cells in culture [82
, 83
, 91
]. Sugita and colleagues [82
, 83
] suggest that the ability of ocular PE to suppress T effector cell activity and to convert activated T cells into regulators is an immune-privilege strategy to limit immunogenic inflammation in the eye.
Iris PE (IPE) are unique from other PE in the eye, as unlike ciliary body PE (CBPE) and retina PE (RPE), IPE use a cell surface, contact-dependent mechanism exclusively to suppress T cell activation in vitro [82
]. Fresh and cultured IPE constitutively express B7-1 and B7-2 on their surface and are necessary to convert naïve T cells to Treg cells. T cells that are converted are CD8+ and express CTLA-4. Soluble factors are also involved in PE suppression, as neutralizing TGF-ß antibody allowed for anti-CD3 activation of naïve cells, even in the presence of IPE in the cultures. A role for membrane-bound TGF-ß [92
] was tested in a subsequent paper [93
]. In that report, it was shown that IPE, through their costimulatory molecules, B7-1 and B7-2, make contact with CTLA-4 on a subpopulation of CD8+ T cells, and when engaged, IPE membrane-associated, active TGF-ß was delivered precisely to the T cells. The targeted CD8+ T cells (IPE Treg) in turn up-regulated expression of their B7 molecules and TGF-ß1/TGF-ß2. The membrane-associated TGF-ß may be as important as the soluble form in maintaining the privilege of the eye. Thus IPE, CBPE, and RPE secrete soluble, active TGF-ß, but in the case of IPE, some of the active molecules are functioning on the cell surface. Cells that expressed a dominant/negative TGF-ßRII were incapable of being suppressed when exposed to IPE. Histological analysis showed that the surface TGF-ß on IPE was uneven and localized to punctate areas on the adjacent T cells, where TGF-ßRII colocalized.
There are many reports that show that Tregs express surface TGF-ß and secrete a soluble form [92
, 94
95
96
97
98
99
]. However, it has also been reported that CD4+ CD25+ Tregs suppress in the absence of TGF-ß [100
]. As active, soluble TGF-ß may be deleterious as well as suppressive and contributes to scarring, a mechanism, whereby the TGF-ß may be activated but controlled within punctuate areas on the cells, may be a more secure way of allowing suppression on a cell-to-cell basis [93
].
|
SUMMARY
|
|---|
Treg cells play a major role in induction and maintenance of suppressed immune inflammation in the eye. The down-regulation of immune inflammation in the eye is a major mechanism of creating the immune-privileged microenvironment. In the ACAID model for studying immune privilege in the eye, two types of Treg cells emerge in the periphery (spleen): afferent CD4+ Treg cells and efferent CD8+ Treg cells. The ACAID CD4+ Treg cells are not dependent on the natural CD4+ CD25+ Treg for generation and consist of two populations: CD4+ CD25+ Foxp3+ Treg and CD4+ CD25+ Tregs. Both of the CD4+ Treg subpopulations are capable of antigen-specific suppression. ACAID CD8+ Tregs appear to suppress CD4+ effector cells directly or through interaction with the APC. It is interesting that the development of the CD8+ Treg is not dependent on CD4+ T cell help for their generation, as ACAID CD8+ Tregs are generated in Class II KO mice, which lack classical CD4+ T cells.
In addition to the Tregs that are generated in the periphery post-introduction of antigen into the eye, Tregs may be generated within the eye by their exposure to locally derived -MSH, and -MSH-dependent CD4+ CD25+ Tregs are thought to re-establish immune regulation in mouse models of autoimmune uveitis. Stromal cells within the eye, such as PE cells, can induce Treg cells via cell-cell contact or soluble factors. It is surprising that IPE and RPE cells express B7 molecules and can modulate CD8+ T cell behavior via ligation of these molecules with surface CTLA-4 molecules expressed by the activated T cell. Another cell-cell contact mechanism for the generation of Treg cells is via membrane-bound TGF-ß on PE cells. Of course, the release of soluble TGF-ß may also be involved in these local mechanisms of immune inflammatory regulation within the eye. Although the regulatory networks described in the review are functioning in the eye or the periphery after intrusion into the eye, the mechanisms are applicable to other organs and tissues. Clearly, the ACAID mechanism is applicable, at least in part, to oral tolerance. And -MSH, a suppressive neuropeptides active in the eye, is found throughout the body, it too may work in the periphery, perhaps by converting primed T cells to regulatory cells.
Received June 8, 2006;
revised October 18, 2006;
accepted October 25, 2006.
|
REFERENCES
|
|---|
- Villasenor, J., Benoist, C., Mathis, D. (2005) AIRE and APECED: molecular insights into an autoimmune disease Immunol. Rev. 204,156-164[CrossRef][Medline]
- Shevach, E. M., McHugh, R. S., Piccirillo, C. A., Thornton, A. M. (2001) Control of T-cell activation by CD4+ CD25+ suppressor T cells Immunol. Rev. 182,58-67[CrossRef][Medline]
- Wood, K. J., Sakaguchi, S. (2003) Regulatory T cells in transplantation tolerance Nat. Rev. Immunol. 3,199-210[CrossRef][Medline]
- Jiang, H., Kashleva, H., Xu, L. X., Forman, J., Flaherty, L., Pernis, B., Braunstein, N. S., Chess, L. (1998) T cell vaccination induces T cell receptor Vß-specific Qa-1-restricted regulatory CD8(+) T cells Proc. Natl. Acad. Sci. USA 95,4533-4537[Abstract/Free Full Text]
- Hu, D., Ikizawa, K., Lu, L., Sanchirico, M. E., Shinohara, M. L., Cantor, H. (2004) Analysis of regulatory CD8 T cells in Qa-1-deficient mice Nat. Immunol. 5,516-523[CrossRef][Medline]
- Eardley, D. D., Hugenberger, J., McVay-Boudreau, L., Shen, F. W., Gershon, R. K., Cantor, H. (1978) Innunoregulatory circuts among T-cell sets. I. T-helper cells induce other T-cell sets to exert feedback inhibition J. Exp. Med. 147,1106-1115[Abstract/Free Full Text]
- Cantor, H., Hugenburger, J., McVay-Boudreau, L., Eardley, D. D., Kemp, J., Shen, F. W., Gershon, R. K. (1978) Immmunoregulatory circuts among T-cell sets. Identification of a subpopulation of T-helper cell that induces feedback inhibition J. Exp. Med. 148,871-877[Abstract/Free Full Text]
- Cassis, L., Aiello, S., Noris, M. (2005) Natural versus adaptive regulatory T cells Contrib. Nephrol. 146,121-131[Medline]
- Piccirillo, C. A., Shevach, E. M. (2004) Naturally-occurring CD4+CD25+ immunoregulatory T cells: central players in the arena of peripheral tolerance Semin. Immunol. 16,81-88[CrossRef][Medline]
- Shevach, E. M. (2002) CD4+CD25+ suppressor T cells: more questions than answers Nat. Rev. Immunol. 2,389-400[Medline]
- Sarantopoulos, S., Lu, L., Cantor, H. (2004) Qa-1 restriction of CD8+ suppressor T cells J. Clin. Invest. 114,1218-1221[CrossRef][Medline]
- Noble, A., Zhao, Z. S., Cantor, H. (1998) Suppression of immune responses by CD8 cells II Qa-1 on activated B cells stimulates CD8 cell suppression of T helper 2 responses J. Immunol. 160,566-571[Abstract/Free Full Text]
- Jiang, H., Wu, Y., Liang, B., Zheng, Z., Tang, G., Kanellopoulos, J., Soloski, M., Winchester, R., Goldstein, I., Chess, L. (2005) An affinity/avidity model of peripheral T cell regulation J. Clin. Invest. 115,302-312[CrossRef][Medline]
- Chess, L., Jiang, H. (2004) Resurrecting CD8+ suppressor T cells Nat. Immunol. 5,469-471[CrossRef][Medline]
- Wang, H. Y., Lee, D. A., Peng, G., Guo, Z., Li, Y., Kiniwa, Y., Shevach, E. M., Wang, R. F. (2004) Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy Immunity 20,107-118[CrossRef][Medline]
- Sakaguchi, S. (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self Nat. Immunol. 6,345-352[CrossRef][Medline]
- Paust, S., Cantor, H. (2005) Regulatory T cells and autoimmune disease Immunol. Rev. 204,195-207[CrossRef][Medline]
- Fontenot, J. D., Gavin, M. A., Rudensky, A. Y. (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells Nat. Immunol. 4,330-336[CrossRef][Medline]
- Hori, S., Nomura, T., Sakaguchi, S. (2003) Control of regulatory T cell development by the transcription factor Foxp3 Science 299,1057-1061[Abstract/Free Full Text]
- McHugh, R. S., Whitters, M. J., Piccirillo, C. A., Young, D. A., Shevach, E. M., Collins, M., Byrne, M. C. (2002) CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor Immunity 16,311-323[CrossRef][Medline]
- Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y., Sakaguchi, S. (2002) Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance Nat. Immunol. 3,135-142[CrossRef][Medline]
- Stevens, R. B., Sutherland, D. E. R., Ansite, J. D., Saxena, M., Rossini, T. J., Levay-Young, B. K., Hering, B. J., Mills, C. D. (1997) Insulin down-regulates the inducible nitric oxide synthase pathway: nitric oxide as cause and effect of diabetes? J. Immunol. 159,5329-5335[Abstract]
- Peng, Y., Laouar, Y., Li, M. O., Green, E. A., Flavell, R. A. (2004) TGF-ß regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes Proc. Natl. Acad. Sci. USA 101,4572-4577[Abstract/Free Full Text]
- Barrat, F. J., Cua, D. J., Boonstra, A., Richards, D. F., Crain, C., Savelkoul, H. F., de Wal-Malefyt, R., Coffman, R. L., Hawrylowicz, C. M., Garra, A. O. (2002) In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines J. Exp. Med. 195,603-616[Abstract/Free Full Text]
- Vieira, P. L., Christensen, J. R., Minaee, S., O’Neill, E. J., Barrat, F. J., Boonstra, A., Barthlott, T., Stockinger, B., Wraith, D. C., O’Garra, A. (2004) IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells J. Immunol. 172,5986-5993[Abstract/Free Full Text]
- Sonoda, K-H., Faunce, D. E., Taniguchi, M., Exley, M., Balk, S., Stein-Streilein, J. (2001) NKT cell-derived IL-10 is essential for the differentiation of antigen-specific T regulatory cells in systemic tolerance J. Immunol. 166,42-50[Abstract/Free Full Text]
- Grohmann, U., Orabona, C., Fallarino, F., Vacca, C., Calcinaro, F., Falorni, A., Candeloro, P., Belladonna, M. L., Bianchi, R., Fioretti, M. C., Puccetti, P. (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo Nat. Immunol. 3,1097-1101[CrossRef][Medline]
- Walsh, P. T., Taylor, D. K., Turka, L. A. (2004) Tregs and transplantation tolerance J. Clin. Invest. 114,1398-1403[CrossRef][Medline]
- Jiang, H., Chess, L. (2004) An integrated view of suppressor T cell subsets in immunoregulation J. Clin. Invest. 114,1198-1208[CrossRef][Medline]
- Field, A. C., Caccavelli, L., Bloch, M. F., Bellon, B. (2003) Regulatory CD8+ T cells control neonatal tolerance to a Th2-mediated autoimmunity J. Immunol. 170,2508-2515[Abstract/Free Full Text]
- Stein-Streilein, J., Streilein, J. W. (2002) Anterior chamber associated immune deviation (ACAID); regulation, biological relevance, and implications for therapy Int. Rev. Immunol. 21,123-152[CrossRef][Medline]
- Zhou, J., Carr, R. I., Liwski, R. S., Stadnyk, A. W., Lee, T. D. (2001) Oral exposure to alloantigen generates intragraft CD8+ regulatory cells J. Immunol. 167,107-113[Abstract/Free Full Text]
- Seino, K. I., Fukao, K., Muramoto, K., Yanagisawa, K., Takada, Y., Katuta, T., Iwakura, Y., Van Kaer, L., Takeda, K., Nakayama, T., Taniguchi, M., Bashuda, H., Yazgita, H., Okumura, K. (2001) Requirement for natural killer T (NKT) cells in the induction of allograft tolerance Proc. Natl. Acad. Sci. USA 98,2577-2581[Abstract/Free Full Text]
- Sonoda, K-H., Exley, M., Snapper, S., Balk, S., Stein-Streilein, J. (1999) CD1 reactive NKT cells are required for development of systemic tolerance through an immune privileged site J. Exp. Med. 190,1215-1225[Abstract/Free Full Text]
- Zhang, Z-X., Yang, L., Young, K. J., DuTemple, B., Zhang, L. (2000) Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression Nat. Med. 6,782-789[CrossRef][Medline]
- Li, M. O., Wan, Y. Y., Sanjabi, S., Robertson, A. K., Flavell, R. A. (2006) Transforming growth factor-ß regulation of immune responses Annu. Rev. Immunol. 24,99-146[CrossRef][Medline]
- Margalit, M., Ilan, Y. (2005) Induction of immune tolerance: a role for natural killer T lymphocytes? Liver Int. 25,501-504[CrossRef][Medline]
- Matzinger, P. (1994) Tolerance, danger, and the extended family Annu. Rev. Immunol. 12,991-1045[Medline]
- Medawar, P. B. (1948) Immunity to homologous grafted skin. III. The fate of skin homografts transplanted to the brain, to subcutaneous tissue and to the anterior chamber of the eye Br. J. Exp. Pathol. 29,58-69
- Medawar, P. B. (1945) A second study of the behavior and fate of skin homografts in rabbits: a report to the War Wounds Committee of the Medical Research Council J. Anat. 79,157-176
- Streilein, J. W. (2003) Ocular immune privilege: therapeutic opportunities from an experiment of nature Nat. Rev. Immunol. 3,879-889[CrossRef][Medline]
- Niederkorn, J. Y. (2006) See no evil, hear no evil, do no evil: the lessons of immune privilege Nat. Immunol. 7,354-359[CrossRef][Medline]
- Schuppe, H. C., Meinhardt, A. (2005) Immune privilege and inflammation of the testis Chem. Immunol. Allergy 88,1-14[CrossRef][Medline]
- Nasr, I. W., Wang, Y., Gao, G., Deng, S., Diggs, L., Rothstein, D. M., Tellides, G., Lakkis, F. G., Dai, Z. (2005) Testicular immune privilege promotes transplantation tolerance by altering the balance between memory and regulatory T cells J. Immunol. 174,6161-6168[Abstract/Free Full Text]
- Dai, Z., Nasr, I. W., Reel, M., Deng, S., Diggs, L., Larsen, C. P., Rothstein, D. M., Lakkis, F. G. (2005) Impaired recall of CD8 memory T cells in immunologically privileged tissue J. Immunol. 174,1165-1170[Abstract/Free Full Text]
- Suter, T., Biolaz, G., Gatto, D., Bernasconi, L., Herren, T., Reith, W., Fontana, A. (2003) The brain as an immune privileged site: dendritic cells of the central nervous system inhibit T cell activation Eur. J. Immunol. 33,2998-3006[CrossRef][Medline]
- Wenkel, H., Streilein, J. W., Young, M. J. (2000) Systemic immune deviation in the brain that does not depend on the integrity of the blood-brain barrier J. Immunol. 164,5125-5131[Abstract/Free Full Text]
- Ksander, B. R., Streilein, J. W. (1994) Regulation of the immune response within privileged sites Chem. Immunol. 58,117-145[Medline]
- Katagiri, K., Zhang-Hoover, J., Mo, J. S., Stein-Streilein, J., Streilein, J. W. (2002) Using tolerance induced via the anterior chamber of the eye to inhibit Th2-dependent pulmonary pathology J. Immunol. 169,84-89[Abstract/Free Full Text]
- Zhang-Hoover, J., Finn, P., Stein-Streilein, J. (2005) Modulation of ovalbumin-induced airway inflammation and hyperreactivity by tolerogenic APC J. Immunol. 175,7117-7124[Abstract/Free Full Text]
- Wilbanks, G. A., Streilein, J. W. (1990) Characterization of suppressor cells in anterior chamber-associated immune deviation (ACAID) induced by soluble antigen. Evidence of two functionally and phenotypically distinct T-suppressor cell populations Immunology 71,383-389[Medline]
- Keino, H., Takeuchi, M., Kezuka, T., Hattori, T., Usui, M., Taguchi, O., Streilein, J. W., Stein-Streilein, J. (2006) Induction of eye-derived tolerance does not depend on naturally occurring CD4+CD25+ T regulatory cells Invest. Ophthalmol. Vis. Sci. 47,1047-1055[Abstract/Free Full Text]
- Keino, H., Masli, S., Sasaki, S., Streilein, J. W., Stein-Streilein, J. (2006) CD8+ T regulatory cells use a novel genetic program that includes CD103 to suppress Th1 immunity in eye-derived tolerance Invest. Ophthalmol. Vis. Sci. 47,1533-1542[Abstract/Free Full Text]
- Faunce, D. E., Stein-Streilein, J. (2002) NKT cell-derived RANTES recruits APCs and CD8+ T cells to the spleen during the generation of regulatory T cells in tolerance J. Immunol. 169,31-38[Abstract/Free Full Text]
- Faunce, D. E., Sonoda, K-H., Stein-Streilein, J. (2001) MIP-2 recruits NKT cells to the spleen during tolerance induction J. Immunol. 166,313-321[Abstract/Free Full Text]
- Sonoda, K-H., Stein-Streilein, J. (2002) CD1d on antigen-transporting APC and splenic marginal zone B cells promotes NKT cell-dependent tolerance Eur. J. Immunol. 32,848-857[CrossRef][Medline]
- Lin, H. H., Faunce, D. E., Stacey, M., Terajewicz, A., Nakamura, T., Zhang-Hoover, J., Kerley, M., Mucenski, M. L., Gordon, S., Stein-Streilein, J. (2005) The macrophage F4/80 receptor is required for the induction of antigen-specific efferent regulatory T cells in peripheral tolerance J. Exp. Med. 201,1615-1625[Abstract/Free Full Text]
- Roelofs-Haarhuis, K., Wu, X., Gleichmann, E. (2004) Oral tolerance to nickel requires CD4+ invariant NKT cells for the infectious spread of tolerance and the induction of specific regulatory T cells J. Immunol. 173,1043-1050[Abstract/Free Full Text]
- Nakamura, T., Sonoda, K. H., Faunce, D. E., Gumperz, J., Yamamura, T., Miyake, S., Stein-Streilein, J. (2003) CD4+ NKT cells, but not conventional CD4+ T cells, are required to generate efferent CD8+ T regulatory cells following antigen inoculation in an immune privileged site J. Immunol. 171,1266-1271[Abstract/Free Full Text]
- Riedl, E., Stockl, J., Majdic, O., Scheinecker, C., Rappersberger, K., Knapp, W., Strobl, H. (2000) Functional involvement of E-cadherin in TGF-ß 1-induced cell cluster formation of in vitro developing human Langerhans-type dendritic cells J. Immunol. 165,1381-1386[Abstract/Free Full Text]
- Higgins, J. M., Mandlebrot, D. A., Shaw, S. K., Russell, G. J., Murphy, E. A., Chen, Y. T., Nelson, W. J., Parker, C. M., Brenner, M. B. (1998) Direct and regulated interaction of integrin Eß7 with E-cadherin J. Cell Biol. 140,197-210[Abstract/Free Full Text]
- Huehn, J., Siegmund, K., Lehmann, J. C., Siewert, C., Haubold, U., Feuerer, M., Debes, G. F., Lauber, J., Frey, O., Przybylski, G. K., Niesner, U., de la Rosa, M., Schmidt, C. A., Brauer, R., Buer, J., Scheffold, A., Hamann, A. (2004) Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells J. Exp. Med. 199,303-313[Abstract/Free Full Text]
- Cousins, S. W., McCabe, M. M., Danielpour, D., Streilein, J. W. (1991) Identification of transforming growth factor-ß as an immunosuppressive factor in aqueous humor Invest. Ophthalmol. Vis. Sci. 32,2201-2211[Abstract/Free Full Text]
- Taylor, A. W. (1999) Ocular immunosuppressive microenvironment Chem. Immunol. 73,72-89[Medline]
- Streilein, J. W. (1999) Immunoregulatory mechanisms of the eye Prog. Retin. Eye Res. 18,357-370[CrossRef][Medline]
- Kingsley, D. M. (1994) The TGF-ß superfamily: new members, new receptors, and new genetic tests of function in different organisms Genes Dev. 8,133-146[Free Full Text]
- Lowrance, J. H., O’Sullivan, F. X., Caver, T. E., Waegell, W., Gresham, H. D. (1994) Spontaneous elaboration of transforming growth factor ß suppresses host defense against bacterial infection in autoimmune MRL/lpr mice J. Exp. Med. 180,1693-1703[Abstract/Free Full Text]
- Cousins, S. W., Trattler, W. B., Streilein, J. W. (1991) Immune privilege and suppression of immunogenic inflammation in the anterior chamber of the eye Curr. Eye Res. 10,287-297[Medline]
- Taylor, A. (2003) A review of the influence of aqueous humor on immunity Ocul. Immunol. Inflamm. 11,231-241[CrossRef][Medline]
- Taylor, A. W., Streilein, J. W., Cousins, S. W. (1992) Identification of -melanocyte stimulating hormone as a potential immunosuppressive factor in aqueous humor Curr. Eye Res. 11,1199-1206[Medline]
- Nishida, T., Taylor, A. W. (1999) Specific aqueous humor factors induce activation of regulatory T cells Invest. Ophthalmol. Vis. Sci. 40,2268-2274[Abstract/Free Full Text]
- Taylor, A. W., Streilein, J. W., Cousins, S. W. (1994) -Melanocyte-stimulating hormone suppresses antigen-stimulated T cell production of -interferon Neuroimmunomodulation 1,188-194[Medline]
- Lee, T. H., Lerner, A. B., Buettner-Janusch, V. (1961) The isolation and structure of - and ß-melanocyte-stimulating hormones from monkey pituitary glands J. Biol. Chem. 236,1390-1394[Free Full Text]
- Watanabe, T., Hiltz, M. E., Catania, A., Lipton, J. M. (1993) Inhibition of IL-1 ß-induced peripheral inflammation by peripheral and central administration of analogs of the neuropeptide -MSH Brain Res. Bull. 32,311-314[CrossRef][Medline]
- Chiao, H., Foster, S., Thomas, R., Lipton, J., Star, R. A. (1996) -Melanocyte-stimulating hormone reduces endotoxin-induced liver inflammation J. Clin. Invest. 97,2038-2044[Medline]
- Rajora, N., Ceriani, G., Catania, A., Star, R. A., Murphy, M. T., Lipton, J. M. (1996) -MSH production, receptors, and influence on neopterin in a human monocyte/macrophage cell line J. Leukoc. Biol. 59,248-253[Abstract]
- Star, R. A., Rajora, N., Huang, J., Stock, R. C., Catania, A., Lipton, J. M. (1995) Evidence of autocrine modulation of macrophage nitric oxide synthase by -melanocyte-stimulating hormone Proc. Natl. Acad. Sci. USA 92,8016-8020[Abstract/Free Full Text]
- Taylor, A. W., Kitaichi, N., Taylor, A. W. (2006) Melanocortin 5 receptor and ocular immunity Cell. Mol. Biol. (Noisy-le-grand) 52,53-59
- Taylor, A., Namba, K. (2001) In vitro induction of CD25+ CD4+ regulatory T cells by the neuropeptide -melanocyte stimulating hormone (-MSH) Immunol. Cell Biol. 79,358-367[CrossRef][Medline]
- Kitaichi, N., Namba, K., Taylor, A. W. (2005) Inducible immune regulation following autoimmune disease in the immune-privileged eye J. Leukoc. Biol. 77,496-502[Abstract/Free Full Text]
- Streilein, J. W., Masli, S., Takeuchi, M., Kezuka, T. (2002) The eye’s view of antigen presentation Hum. Immunol. 63,435-445[CrossRef][Medline]
- Sugita, S., Streilein, J. W. (2003) Iris pigment epithelium expressing CD86 (B7–2) directly suppresses T cell activation in vitro via binding to cytotoxic T lymphocyte-associated antigen 4 J. Exp. Med. 198,161-171[Abstract/Free Full Text]
- Sugita, S., Ng, T. F., Schwartzkopff, J., Streilein, J. W. (2004) CTLA-4+CD8+ T cells that encounter B7–2+ iris pigment epithelial cells express their own B7–2 to achieve global suppression of T cell activation J. Immunol. 172,4184-4194[Abstract/Free Full Text]
- Yoshida, M., Kezuka, T., Streilein, J. W. (2000) Participation of pigment epithelium of iris and ciliary body in ocular immune privilege. 2. Generation of TGF-ß-producing regulatory T cells Invest. Ophthalmol. Vis. Sci. 41,3862-3870[Abstract/Free Full Text]
- Yoshida, M., Takeuchi, M., Streilein, J. W. (2000) Participation of pigment epithelium of iris and ciliary body in ocular immune privilege. 1. Inhibition of T-cell activation in vitro by direct cell-to-cell contact Invest. Ophthalmol. Vis. Sci. 41,811-821[Abstract/Free Full Text]
- Bora, N. S., Gobleman, C. L., Atkinson, J. P., Pepose, J. S., Kaplan, H. J. (1993) Differential expression of the complement regulatory proteins in the human eye Invest. Ophthalmol. Vis. Sci. 34,3579-3584[Abstract/Free Full Text]
- Griffith, T. S., Brunner, T., Fletcher, S. M., Green, D. R., Ferguson, T. A. (1995) Fas ligand-induced apoptosis as a mechanism of immune privilege Science 270,1189-1192[Abstract/Free Full Text]
- Sonoda, K. H., Sakamoto, T., Qiao, H., Hisatomi, T., Oshima, T., Tsutsumi-Miyahara, C., Exley, M., Balk, S. P., Taniguchi, M., Ishibashi, T. (2005) The analysis of systemic tolerance elicited by antigen inoculation into the vitreous cavity: vitreous cavity-associated immune deviation Immunology 116,390-399[CrossRef][Medline]
- Wenkel, H., Chen, P. W., Ksander, B. R., Streilein, J. W. (1999) Immune privilege is extended, then withdrawn, from allogeneic tumor cell grafts placed in the subretinal space Invest. Ophthalmol. Vis. Sci. 40,3202-3208[Abstract/Free Full Text]
- Streilein, J. W., Ma, N., Wenkel, H., Ng, T. F., Zamiri, P. (2002) Immunobiology and privilege of neuronal retina and pigment epithelium transplants Vision Res. 42,487-495[CrossRef][Medline]
- Ishida, K., Panjwani, N., Cao, Z., Streilein, J. W. (2003) Participation of pigment epithelium in ocular immune privilege. 3. Epithelia cultured from iris, ciliary body, and retina suppress T-cell activation by partially non-overlapping mechanisms Ocul. Immunol. Inflamm. 11,91-105[CrossRef][Medline]
- Nakamura, K., Kitani, A., Strober, W. (2001) Cell contact-dependent immunosuppression by CD4+CD25+ regulatory T cells is mediated by cell surface-bound transforming growth factor ß J. Exp. Med. 194,629-644[Abstract/Free Full Text]
- Sugita, S., Ng, T. F., Lucas, P. J., Gress, R. E., Streilein, J. W. (2006) B7+ iris pigment epithelium induce CD8+ T regulatory cells; both suppress CTLA-4+ T cells J. Immunol. 176,118-127[Abstract/Free Full Text]
- Chen, W., Wahl, S. M. (2003) TGF-ß: the missing link in CD4+CD25+ regulatory T cell-mediated immunosuppression Cytokine Growth Factor Rev. 14,85-89[CrossRef][Medline]
- Levings, M. K., Sangregorio, R., Sartirana, C., Moschin, A. L., Battaglia, M., Orban, P. C., Roncarolo, M. G. (2002) Human CD25+CD4+ T suppressor cell clones produce transforming growth factor ß, but not interleukin 10, and are distinct from type 1 T regulatory cells J. Exp. Med. 196,1335-1346[Abstract/Free Full Text]
- Nakamura, K., Kitani, A., Fuss, I., Pedersen, A., Harada, N., Nawata, H., Strober, W. (2004) TGF-ß 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice J. Immunol. 172,834-842[Abstract/Free Full Text]
- Zheng, S. G., Gray, J. D., Ohtsuka, K., Yamagiwa, S., Horwitz, D. A. (2002) Generation ex vivo of TGF-ß-producing regulatory T cells from CD4+CD25– precursors J. Immunol. 169,4183-4189[Abstract/Free Full Text]
- Cosmi, L., Liotta, F., Lazzeri, E., Francalanci, M., Angeli, R., Mazzinghi, B., Santarlasci, V., Manetti, R., Vanini, V., Romagnani, P., Maggi, E., Romagnani, S., Annunziato, F. (2003) Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes Blood 102,4107-4114[Abstract/Free Full Text]
- Chen, W., Jin, W., Hardegen, N., Lei, K. J., Li, L., Marinos, N., McGrady, G., Wahl, S. M. (2003) Conversion of peripheral CD4+CD25– naive T cells to CD4+CD25+ regulatory T cells by TGF-ß induction of transcription factor Foxp3 J. Exp. Med. 198,1875-1886[Abstract/Free Full Text]
- Piccirillo, C. A., Letterio, J. J., Thornton, A. M., McHugh, R. S., Mamura, M., Mizuhara, H., Shevach, E. M. (2002) CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor ß1 production and responsiveness J. Exp. Med. 196,237-246[Abstract/Free Full Text]
TOP
ABSTRACT
INTRODUCTION
