CD8+ T Regulatory Cells in Eye Derive Tolerance



Regulatory T cells or Tregs are critical to the development of self-tolerance and a natural way to terminate an immune response. While most studies are directed toward understanding thymic-derived natural afferent CD4+ CD25+ Tregs that regulate induction of immune responses, our studies focus on the antigen specific efferent CD8+ Treg cells that develop in the periphery and limit immune responses during their effector stage. The development of CD8+ Treg cells is one of the mechanisms that contribute to the eye being an immune privileged site. Immune privilege is a term that is associated with sites and tissue that enjoy long-term survival of tissue grafts of foreign derivation. Immune privilege is a dynamic process that allows for immune responses that lack inflammation thus permitting immune protection in the absence of tissue damage. A model to study immune privilege is called anterior chamber associated immune deviation or ACAID. Through the study of ACAID, cellular and molecular mechanisms were observed that show that the development of CD8+ Treg cells post intracameral inoculation of antigen is dependent on specialized antigen presenting cells (F4/80+ APC), NKT cells, T cells and, marginal zone derived B cells that meet not in the T cell areas of the secondary lymphoid tissue but in the marginal zone of the spleen. These studies were expanded by recent investigations that explored the mechanisms used by CD8+ Treg cells to regulate immune CD4+ T cell effector function. Understanding how to generate efferent Treg cells that limit ongoing immune inflammation may lead to novel therapy for immune inflammatory diseases in the eye and the periphery.


Treg Cell Pigment Epithelium iNKT Cell Immune Privilege Immune Privileged Site 



The authors thank Ms. Amelia Margolis for her assistance with the preparation of this review. We also thank Peter Mallen for the graphics prepared for this manuscript.

Funding: Research supported by grants from the NIH, EY11983 and EY016476.

Joan Stein-Streilein Patent Pending (#10/468,944)


  1. 1.
    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.PubMedGoogle Scholar
  2. 2.
    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: 157–188.Google Scholar
  3. 3.
    Matzinger, P. 1994. Tolerance, danger, and the extended family. Annu Rev Immunol 12: 991–1045.PubMedCrossRefGoogle Scholar
  4. 4.
    Niederkorn, J. Y. 2006. See no evil, hear no evil, do no evil: the lessons of immune privilege. Nat Immunol 7:354–359.PubMedCrossRefGoogle Scholar
  5. 5.
    Schuppe, H. C., and A. Meinhardt. 2005. Immune privilege and inflammation of the testis. Chem Immunol Allergy 88:1–14.PubMedCrossRefGoogle Scholar
  6. 6.
    Nasr, I. W., Y. Wang, G. Gao, S. Deng, L. Diggs, D. M. Rothstein, G. Tellides, F. G. Lakkis, and Z. Dai. 2005. Testicular immune privilege promotes transplantation tolerance by altering the balance between memory and regulatory T cells. J Immunol 174:6161–6168.PubMedGoogle Scholar
  7. 7.
    Dai, Z., I. W. Nasr, M. Reel, S. Deng, L. Diggs, C. P. Larsen, D. M. Rothstein, and F. G. Lakkis. 2005. Impaired recall of CD8 memory T cells in immunologically privileged tissue. J Immunol 174:1165–1170.PubMedGoogle Scholar
  8. 8.
    Suter, T., G. Biolaz, D. Gatto, L. Bernasconi, T. Herren, W. Reith, and A. Fontana. 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.Google Scholar
  9. 9.
    Wenkel, H., J. W. Streilein, and M. J. Young. 2000. Systemic immune deviation in the brain that does not depend on the integrity of the blood-brain barrier. J Immunol 164:5125–5131.PubMedGoogle Scholar
  10. 10.
    Ksander, B. R., and J. W. Streilein. 1994. Regulation of the immune response within privileged sites. Chem Immunol 58:117–145.PubMedCrossRefGoogle Scholar
  11. 11.
    Kaplan, H. J., J. W. Streilein, and T. R. Stevens. 1975. Transplantation immunology of the anterior chamber of the eye. II. Immmune response to allogeneic cells. J Immunol 118:809–814.Google Scholar
  12. 12.
    Streilein, J. W. 2003. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol 3:878–889.CrossRefGoogle Scholar
  13. 13.
    Katagiri, K., J. Zhang-Hoover, J. S. Mo, J. Stein-Streilein, and J. W. Streilein. 2002. Using tolerance induced via the anterior chamber of the eye to inhibit Th2-dependent pulmonary pathology. J Immunol 169:84–89.PubMedGoogle Scholar
  14. 14.
    Zhang-Hoover, J., P. Finn, and J. Stein-Streilein. 2005. Modulation of ovalbumin-induced airway inflammation and hyperreactivity by tolerogenic APC. J Immunol 175:7117–7124.PubMedGoogle Scholar
  15. 15.
    Stein-Streilein, J. 2005. A privileged view of NKT cells and peripheral tolerance through the eye. Ocul Immunol Inflamm 13:111–117.PubMedCrossRefGoogle Scholar
  16. 16.
    Stein-Streilein, J., and A. W. Taylor. 2007. An eye's view of T regulatory cells. J Leukoc Biol 81:593–598.PubMedCrossRefGoogle Scholar
  17. 17.
    Stein-Streilein, J., and C. Watte. 2007. Cross Talk among Cells Promoting Anterior Chamber-Associated Immune Deviation. Chem Immunol Allergy 92:115–130.PubMedCrossRefGoogle Scholar
  18. 18.
    Zhang-Hoover, J., and J. Stein-Streilein. 2007. Therapies based on principles of ocular immune privilege. Chem Immunol Allergy 92:317–327.PubMedCrossRefGoogle Scholar
  19. 19.
    Niederkorn, J. Y. 2002. Immune privilege in the anterior chamber of the eye. Crit Rev Immunol 22:13–46.PubMedGoogle Scholar
  20. 20.
    Faunce, D. E., K.-H. Sonoda, and J. Stein-Streilein. 2001. See reference 6678. J Immunol 166:313–321.PubMedGoogle Scholar
  21. 21.
    Wang, Y., I. Goldschneider, J. O'Rourke, and R. E. Cone. 2001. Blood mononuclear cells induce regulatory NK T thymocytes in anterior chamber-associated immune deviation. J Leukoc Biol 69:741–746.PubMedGoogle Scholar
  22. 22.
    Streilein, J. W. 2003. Ocular immune privilege: the eye takes a dim but practical view of immunity and inflammation. J Leukoc Biol 74:179–185.PubMedCrossRefGoogle Scholar
  23. 23.
    Wilbanks, G. A., and J. W. Streilein. 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.PubMedGoogle Scholar
  24. 24.
    Keino, H., M. Takeuchi, T. Kezuka, T. Hattori, M. Usui, O. Taguchi, J. W. Streilein, and J. Stein-Streilein. 2006. Induction of eye-derived tolerance does not depend on naturally occurring CD4+CD25+ T regulatory cells. Invest Ophthalmol Vis Sci 47:1047–1055.PubMedCrossRefGoogle Scholar
  25. 25.
    Keino, H., S. Masli, S. Sasaki, J. W. Streilein, and J. Stein-Streilein. 2006. CD8∗ T regulatory cells use a novel genetic program that includes CD103 to suppress Th1 immunity in eye-derived tolerance. Invest Ohthalmol Vis Sci 47:1533–1543.CrossRefGoogle Scholar
  26. 26.
    Faunce, D. E., and J. Stein-Streilein. 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.PubMedGoogle Scholar
  27. 27.
    Sonoda, K.-H., and J. Stein-Streilein. 2002. CD1d on antigen-transporting APC and splenic marginal zone B cells promotes NKT cell-dependent tolerance. Eur J Immunol 32:848–857.PubMedCrossRefGoogle Scholar
  28. 28.
    Lin, H. H., D. E. Faunce, M. Stacey, A. Terajewicz, T. Nakamura, J. Zhang-Hoover, M. Kerley, M. L. Mucenski, S. Gordon, and J. Stein-Streilein. 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.PubMedCrossRefGoogle Scholar
  29. 29.
    Roelofs-Haarhuis, K., X. Wu, and E. Gleichmann. 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.PubMedGoogle Scholar
  30. 30.
    Dullforce, P. A., K. L. Garman, G. W. Seitz, R. J. Fleischmann, S. M. Crespo, S. R. Planck, D. C. Parker, and J. T. Rosenbaum. 2004. APCs in the anterior uveal tract do not migrate to draining lymph nodes. J Immunol 172:6701–6708.PubMedGoogle Scholar
  31. 31.
    Hara, Y., R. R. Caspi, B. Wiggert, M. Dorf, and J. W. Streilein. 1992. Analysis of an in vitro-generated signal that induces systemic immune deviation similar to that elicited by antigen injected into the anterior chamber of the eye. J Immunol 149:1531–1538.PubMedGoogle Scholar
  32. 32.
    Sonoda, K.-H., M. Exley, S. Snapper, S. Balk, and J. Stein-Streilein. 1999. CD1 reactive NKT cells are required for development of systemic tolerance through an immune privileged site. J Exp Med 190:1215–1225.PubMedCrossRefGoogle Scholar
  33. 33.
    Nakamura, T., K. H. Sonoda, D. E. Faunce, J. Gumperz, T. Yamamura, S. Miyake, and J. Stein-Streilein. 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.PubMedGoogle Scholar
  34. 34.
    Skelsey, M. E., E. Mayhew, and J. Y. Niederkorn. 2003. CD25+, interleukin-10-producing CD4+ T cells are required for suppressor cell production and immune privilege in the anterior chamber of the eye. Immunol 110:18–29.CrossRefGoogle Scholar
  35. 35.
    Meng, Q., P. Yang, B. Li, H. Zhou, X. Huang, L. Zhu, Y. Ren, and A. Kijlstra. 2006. CD4+PD-1+ T cells acting as regulatory cells during the induction of anterior chamber-associated immune deviation. Invest Ophthalmol Vis Sci 47:4444–4452.PubMedCrossRefGoogle Scholar
  36. 36.
    D'Orazio, T. J., and J. Y. Niederkorn. 1996. A novel role for TGF β and IL-10 in the induction of immune privilege. J Immunol 160:2089–2098.Google Scholar
  37. 37.
    Wilbanks, G. A., and J. W. Streilein. 1991. Studies on the induction of anterior chamber-associated immune deviation (ACAID). I. Evidence that an antigen-specific, ACAID-inducing, cell-associated signal exists in the peripheral blood. J Immunol 146:2610–2617.PubMedGoogle Scholar
  38. 38.
    Wang, Y., I. Goldschneider, D. Foss, D. Y. Wu, J. O'Rourke, and R. E. Cone. 1997. Direct thymic involvement in anterior chamber-associated immune deviation: Evidence for a nondeletional mechanism of centrally induced tolerance to extrathymic antigens in adult mice. J Immunol 158:2150–2155.PubMedGoogle Scholar
  39. 39.
    Kosiewicz, M. M., and P. Alard. 2004. Tolerogenic antigen-presenting cells: regulation of the immune response by TGF-beta-treated antigen-presenting cells. Immunol Res 30:155–170.PubMedCrossRefGoogle Scholar
  40. 40.
    Faunce, D. E., K. H. Sonoda, and J. Stein-Streilein. 2001. MIP-2 recruits NKT cells to the spleen during tolerance induction. J Immunol 166:313–321.PubMedGoogle Scholar
  41. 41.
    D'Orazio, T. J., and J. Y. Niederkorn. 1998. Splenic B cells are required for tolerogenic antigen presentation in the induction of anterior chamber-associated immune deviation (ACAID). Immunology 95:47–55.PubMedCrossRefGoogle Scholar
  42. 42.
    Sonoda, K. H., and J. Stein-Streilein. 2002. CD1d on antigen-transporting APC and splenic marginal zone B cells promotes NKT cell-dependent tolerance. Eur J Immunol 32: 848–857.PubMedCrossRefGoogle Scholar
  43. 43.
    Nowak, M., and J. Stein-Streilein. 2007. Invariant NKT cells and tolerance. Int Rev Immunol 26:95–119.PubMedCrossRefGoogle Scholar
  44. 44.
    Cousins, S. W., M. M. McCabe, D. Danielpour, and J. W. Streilein. 1991. Identification of transforming growth factor-beta as an immunosuppressive factor in aqueous humor. Invest. Ophthalmol. Vis. Sci 32:2201–2211.PubMedGoogle Scholar
  45. 45.
    Taylor, A. W. 1999. Ocular immunosuppressive microenvironment. Chem Immunol 73:72–89.PubMedCrossRefGoogle Scholar
  46. 46.
    Sugita, S., and J. W. Streilein. 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.PubMedCrossRefGoogle Scholar
  47. 47.
    Sugita, S., T. F. Ng, J. Schwartzkopff, and J. W. Streilein. 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.PubMedGoogle Scholar
  48. 48.
    Yoshida, M., T. Kezuka, and J. W. Streilein. 2000. Participation of pigment epithelium of iris and ciliary body in ocular immune privilege. 2. Generation of TGF-beta-producing regulatory T cells. Invest Ophthalmol Vis Sci 41:3862–3870.PubMedGoogle Scholar
  49. 49.
    Yoshida, M., M. Takeuchi, and J. W. Streilein. 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.PubMedGoogle Scholar
  50. 50.
    Bora, N. S., C. L. Gobleman, J. P. Atkinson, J. S. Pepose, and H. J. Kaplan. 1993. Differential expression of the complement regulatory proteins in the human eye. Invest Ophthalmol Vis Sci 34:3579–3584.PubMedGoogle Scholar
  51. 51.
    Griffith, T. S., T. Brunner, S. M. Fletcher, D. R. Green, and T. A. Ferguson. 1995. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 270:1189–1192.PubMedCrossRefGoogle Scholar
  52. 52.
    Streilein, J. W. 1999. Immunoregulatory mechanisms of the eye. Prog Retin Eye Res 18:357–370.PubMedCrossRefGoogle Scholar
  53. 53.
    Kingsley, D. M. 1994. The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev 8:133–146.PubMedCrossRefGoogle Scholar
  54. 54.
    Lowrance, J. H., F. X. O'Sullivan, T. E. Caver, W. Waegell, and H. D. Gresham. 1994. Spontaneous elaboration of transforming growth factor beta suppresses host defense against bacterial infection in autoimmune MRL/lpr mice. J Exp Med 180:1693–1703.PubMedCrossRefGoogle Scholar
  55. 55.
    Cousins, S. W., W. B. Trattler, and J. W. Streilein. 1991. Immune privilege and suppression of immunogenic inflammation in the anterior chamber of the eye. Curr Eye Res 10: 287–297.PubMedCrossRefGoogle Scholar
  56. 56.
    Taylor, A. 2003. A review of the influence of aqueous humor on immunity. Ocul Immunol Inflamm 11:231–241.PubMedCrossRefGoogle Scholar
  57. 57.
    Taylor, A. W., J. W. Streilein, and S. W. Cousins. 1992. Identification of alpha-melanocyte stimulating hormone as a potential immunosuppressive factor in aqueous humor. Current Eye Research 11:1199–1206.PubMedCrossRefGoogle Scholar
  58. 58.
    Huehn, J., K. Siegmund, J. C. Lehmann, C. Siewert, U. Haubold, M. Feuerer, G. F. Debes, J. Lauber, O. Frey, G. K. Przybylski, U. Niesner, M. de la Rosa, C. A. Schmidt, R. Brauer, J. Buer, A. Scheffold, and A. Hamann. 2004. Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells. J Exp Med 199: 303–313.PubMedCrossRefGoogle Scholar
  59. 59.
    Goslings, W. R. O., Prodeus, A.P., Streilein, J. W., Carroll, M. C., Jager, M. S., and Taylor, A. W. 1998. A small molecular weight factor in aqueous humor acts on C1q to prevent antibody-dependent complement activation. Invest Ophthalmol Vis Sci 39:989–995.PubMedGoogle Scholar
  60. 60.
    Lass, L. H., E. I. Walter, T. E. Burris, H. E. Grossniklaus, M. I. Roat, D. l. Skelnik, L. Needham, M. Singer, and M. E. Medof. 1990. Expression of two molecular forms of the complement decay-accelerating factor in the eye and lacrimal gland. Invest Opthahalmol Vis Sci 31:1136–1148.Google Scholar
  61. 61.
    Wilbanks, G. A., and J. W. Streilein. 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.PubMedGoogle Scholar
  62. 62.
    Stein-Streilein, J., and J. W. Streilein. 2002. Anterior chamber associated immune deviation (ACAID); regulation, biological relevance, and implications for therapy. Int Rev Immunol 21:123–152.PubMedCrossRefGoogle Scholar
  63. 63.
    Sonoda, K. H., T. Sakamoto, H. Qiao, T. Hisatomi, T. Oshima, C. Tsutsumi-Miyahara, M. Exley, S. P. Balk, M. Taniguchi, and T. Ishibashi. 2005. The analysis of systemic tolerance elicited by antigen inoculation into the vitreous cavity: vitreous cavity-associated immune deviation. Immunology 116:390–399.PubMedCrossRefGoogle Scholar
  64. 64.
    Wenkel, H., Chen, P.W., Ksander, B.R., and Streilein, J. W. 1999. Immune privilge is extended, then withdrawn, from allogeneic tumor cell grafts place in the subretinal space. Invest Opthahalmol Vis Sci 40:3203–3208.Google Scholar
  65. 65.
    Streilein, J. W., N. Ma, H. Wenkel, T. F. Ng, and P. Zamiri. 2002. Immunobiology and privilege of neuronal retina and pigment epithelium transplants. Vision Res 42:487–495.PubMedCrossRefGoogle Scholar
  66. 66.
    Ishida, K., N. Panjwani, Z. Cao, and J. W. Streilein. 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.PubMedCrossRefGoogle Scholar
  67. 67.
    Nakamura, K., A. Kitani, and W. Strober. 2001. Cell contact-dependent immunosuppression by CD4+CD25+ regulatory T cells is mediated by cell surface-bound transforming growth factor β. J Exp Med 194:629–644.PubMedCrossRefGoogle Scholar
  68. 68.
    Sugita, S., T. F. Ng, P. J. Lucas, R. E. Gress, and J. W. Streilein. 2006. B7+ iris pigment epithelium induce CD8+ T regulatory cells; both suppress CTLA-4+ T cells. J Immunol 176:118–127.PubMedGoogle Scholar
  69. 69.
    Chen, W., and S. M. Wahl. 2003. TGF-beta: the missing link in CD4+CD25+ regulatory T cell-mediated immunosuppression. Cytokine Growth Factor Rev 14:85–89.PubMedCrossRefGoogle Scholar
  70. 70.
    Levings, M. K., R. Sangregorio, C. Sartirana, A. L. Moschin, M. Battaglia, P. C. Orban, and M. G. Roncarolo. 2002. Human CD25+CD4+ T suppressor cell clones produce transforming growth factor beta, but not interleukin 10, and are distinct from type 1 T regulatory cells. J Exp Med 196:1335–1346.PubMedCrossRefGoogle Scholar
  71. 71.
    Nakamura, K., A. Kitani, I. Fuss, A. Pedersen, N. Harada, H. Nawata, and W. Strober. 2004. TGF-beta 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.PubMedGoogle Scholar
  72. 72.
    Zheng, S. G., J. D. Gray, K. Ohtsuka, S. Yamagiwa, and D. A. Horwitz. 2002. Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD25– precursors. J Immunol 169:4183–4189.PubMedGoogle Scholar
  73. 73.
    Cosmi, L., F. Liotta, E. Lazzeri, M. Francalanci, R. Angeli, B. Mazzinghi, V. Santarlasci, R. Manetti, V. Vanini, P. Romagnani, E. Maggi, S. Romagnani, and F. Annunziato. 2003. Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes. Blood 102:4107–4114.PubMedCrossRefGoogle Scholar
  74. 74.
    Chen, W., W. Jin, N. Hardegen, K. J. Lei, L. Li, N. Marinos, G. McGrady, and S. M. Wahl. 2003. Conversion of peripheral CD4+CD25– naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198:1875–1886.PubMedCrossRefGoogle Scholar
  75. 75.
    Piccirillo, C. A., J. J. Letterio, A. M. Thornton, R. S. McHugh, M. Mamura, H. Mizuhara, and E. M. Shevach. 2002. CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. J Exp Med 196:237–246.PubMedCrossRefGoogle Scholar
  76. 76.
    Shevach, E. M. 2002. CD4+CD25+ suppressor T cells: More questions than answers. Nature Rev Immunol 2:389–400.Google Scholar
  77. 77.
    Riedl, E., J. Stockl, O. Majdic, C. Scheinecker, K. Rappersberger, W. Knapp, and H. Strobl. 2000. Functional involvement of E-cadherin in TGF-beta 1-induced cell cluster formation of in vitro developing human Langerhans-type dendritic cells. J Immunol 165:1381–1386.PubMedGoogle Scholar
  78. 78.
    Higgins, J. M., D. A. Mandlebrot, S. K. Shaw, G. J. Russell, E. A. Murphy, Y. T. Chen, W. J. Nelson, C. M. Parker, and M. B. Brenner. 1998. Direct and regulated interaction of integrin alphaEbeta7 with E-cadherin. J Cell Biol 140:197–210.PubMedCrossRefGoogle Scholar
  79. 79.
    Feng, Y., D. Wang, R. Yuan, C. M. Parker, D. L. Farber, and G. A. Hadley. 2002. CD103 expression is required for destruction of pancreatic islet allografts by CD8(+) T cells. J Exp Med 196:877–886.PubMedCrossRefGoogle Scholar
  80. 80.
    Wang, D., R. Yuan, Y. Feng, R. El-Asady, D. L. Farber, R. E. Gress, P. J. Lucas, and G. A. Hadley. 2004. Regulation of CD103 expression by CD8+ T cells responding to renal allografts. J Immunol 172:214–221.PubMedGoogle Scholar
  81. 81.
    Mucida, D., Y. Park, G. Kim, O. Turovskaya, I. Scott, M. Kronenberg, and H. Cheroutre. 2007. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317:256–260.PubMedCrossRefGoogle Scholar
  82. 82.
    Imai, S., M. Okuno, H. Moriwaki, Y. Muto, K. Murakami, K. Shudo, Y. Suzuki, and S. Kojima. 1997. 9,13-di-cis-Retinoic acid induces the production of tPA and activation of latent TGF-beta via RAR alpha in a human liver stellate cell line, LI90. FEBS Lett 411:102–106.PubMedCrossRefGoogle Scholar
  83. 83.
    Webster, N. L., and S. M. Crowe. 2006. Matrix metalloproteinases, their production by monocytes and macrophages and their potential role in HIV-related diseases. J Leukoc Biol 80:1052–1066.PubMedCrossRefGoogle Scholar
  84. 84.
    Dallas, S. L., J. L. Rosser, G. R. Mundy, and L. F. Bonewald. 2002. Proteolysis of latent transforming growth factor-beta (TGF-beta )-binding protein-1 by osteoclasts. A cellular mechanism for release of TGF-beta from bone matrix. J Biol Chem 277:21352–21360.PubMedCrossRefGoogle Scholar
  85. 85.
    Yu, Q., and I. Stamenkovic. 2000. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 14:163–176.PubMedGoogle Scholar
  86. 86.
    Jiang, L., P. Yang, H. He, B. Li, X. Lin, S. Hou, H. Zhou, X. Huang, and K. Aize. 2007. Increased expression of Foxp3 in splenic CD8+ T cells from mice with anterior chamber-associated immune deviation. Mol Vis 13:968–974.PubMedGoogle Scholar
  87. 87.
    Kosiewicz, M. M., S. Okamoto, S. Miki, B. R. Ksander, T. Shimizu, and J. W. Streilein. 1994. Imposing deviant immunity on the presensitized state. J Immunol 153:2962–2973.PubMedGoogle Scholar
  88. 88.
    Okamoto, S., M. M. Kosiewicz, R. R. Caspi, and J. W. Streilein. 1994. ACAID as a potential therapy for establishmental autoimmune uveitis. In Advances in Ocular Immunology. R. B. Nussenblatt, S. M. Whitcup, R. R. Caspi, and I. Gery, eds. Elsevier Science, Amsterdam. 195–198.Google Scholar
  89. 89.
    Faunce, D. E., A. Terajewicz, and J. Stein-Streilein. 2004. Cutting edge: In vitro-generated tolerogenic APC induce CD8+ T regulatory cells that can suppress ongoing experimental autoimmune encephalomyelitis. J Immunol 172:1991–1995.PubMedGoogle Scholar
  90. 90.
    Zhang-Hoover, J., and J. Stein-Streilein. 2004. Tolerogenic APC generate CD8+ T regulatory cells that modulate pulmonary interstitial fibrosis. J Immunol 172:178–185.PubMedGoogle Scholar
  91. 91.
    Yokoi, H., and J. W. Streilein. 2004. Antigen-presenting cells are targets of regulatory T cells similar to those that mediate anterior chamber-associated immune deviation. Ocul Immunol Inflamm 12:101–114.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Schepens Eye Research Institute, Department of OphthalmologyHarvard Medical SchoolBostonUSA

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