Ocular Immune Privilege Sites

  • Sharmila MasliEmail author
  • Jose L. Vega
Part of the Methods in Molecular Biology book series (MIMB, volume 677)


The eye is one of the immune privilege sites of the body that is consequently protected from the detrimental and potentially blinding influences of immunologic inflammation. Within the eye, the anterior chamber has been recognized for its immune privilege property for many years now; however, a similar property detectable in the subretinal space has only recently been appreciated. These ocular sites are not only equipped with specialized mechanisms that barricade local inflammatory responses, but also induce systemic regulatory immune response. Numerous studies have characterized molecular and cellular mechanisms involved in conferring both these sites with an immune privilege status. Pigmented epithelial cells lining the anterior chamber in the iris and ciliary body area as well as those in the retina are endowed with immunomodulatory properties that contribute to ocular immune privilege. These cells, via expression of either soluble factors or membrane molecules, inhibit inflammatory T cell activation and promote the generation of regulatory T cells. In the anterior chamber resident antigen-presenting cells, influenced by the various immunosuppressive factors present in the aqueous humor, capture ocular antigens and present them in the spleen to T cells in association with NKT cells and marginal zone B cells. Immunomodulatory microenvironment created by these cells helps generate regulatory T cells, capable of interrupting the induction as well as expression of inflammatory responses. Furthermore, neural regulation of both intraocular and systemic regulatory mechanisms also contributes to ocular immune privilege.

Key words

Immune privilege Anterior chamber Antigen-presenting cells Thrombospondin Regulatory T cells Ocular sympathetic innervations 


  1. 1.
    Medawar, P. B. (1948) Immunity to homologous grafted skin; 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, 58–69PubMedGoogle Scholar
  2. 2.
    Niederkorn, J., Streilein, J. W., and Shadduck, J. A. (1981) Deviant immune responses to allogeneic tumors injected intracamerally and subcutaneously in mice. Invest Ophthalmol Vis Sci 20, 355–363PubMedGoogle Scholar
  3. 3.
    Jiang, L. Q., Jorquera, M., and Streilein, J. W. (1993) Subretinal space and vitreous cavity as immunologically privileged sites for retinal allografts. Invest Ophthalmol Vis Sci 34, 3347–3354PubMedGoogle Scholar
  4. 4.
    Streilein, J. W., Masli, S., Takeuchi, M., and Kezuka, T. (2002) The eye’s view of antigen presentation. Hum Immunol 63, 435–443PubMedCrossRefGoogle Scholar
  5. 5.
    Taylor, A. W. (2007) Ocular immunosuppressive microenvironment. Chem Immunol Allergy 92, 71–85PubMedCrossRefGoogle Scholar
  6. 6.
    Sugita, S., Futagami, Y., Smith, S. B., Naggar, H., and Mochizuki, M. (2006) Retinal and ciliary body pigment epithelium suppress activation of T lymphocytes via transforming growth factor beta. Exp Eye Res 83, 1459–1471PubMedCrossRefGoogle Scholar
  7. 7.
    Yoshida, M., Takeuchi, M., and 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, 811–821PubMedGoogle Scholar
  8. 8.
    Yoshida, M., Kezuka, T., and Streilein, J. W. (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, 3862–3870PubMedGoogle Scholar
  9. 9.
    Pfeffer, B. A., Flanders, K. C., Guerin, C. J., Danielpour, D., and Anderson, D. H. (1994) Transforming growth factor beta 2 is the predominant isoform in the neural retina, retinal pigment epithelium-choroid and vitreous of the monkey eye. Exp Eye Res 59, 323–333PubMedCrossRefGoogle Scholar
  10. 10.
    Usui, Y., Okunuki, Y., Hattori, T., Kezuka, T., Keino, H., Ebihara, N., Sugita, S., Usui, M., Goto, H., and Takeuchi, M. (2008) Functional expression of B7H1 on retinal pigment epithelial cells. Exp Eye Res 86, 52–59PubMedCrossRefGoogle Scholar
  11. 11.
    Sugita, S., Horie, S., Nakamura, O., Futagami, Y., Takase, H., Keino, H., Aburatani, H., Katunuma, N., Ishidoh, K., Yamamoto, Y., and Mochizuki, M. (2008) Retinal pigment epithelium-derived CTLA-2alpha induces TGFbeta-producing T regulatory cells. J Immunol 181, 7525–7536PubMedGoogle Scholar
  12. 12.
    Wenkel, H., and Streilein, J. W. (2000) Evidence that retinal pigment epithelium functions as an immune-privileged tissue. Invest Ophthalmol Vis Sci 41, 3467–3473PubMedGoogle Scholar
  13. 13.
    Saika, S. (2006) TGFbeta pathobiology in the eye. Lab Invest 86, 106–115PubMedCrossRefGoogle Scholar
  14. 14.
    Wilbanks, G. A., and Streilein, J. W. (1990) Distinctive humoral immune responses following anterior chamber and intravenous administration of soluble antigen. Evidence for active suppression of IgG2-secreting B lymphocytes. Immunology 71, 566–572PubMedGoogle Scholar
  15. 15.
    Ksander, B. R., and Streilein, J. W. (1989) Analysis of cytotoxic T cell responses to intracameral allogeneic tumors. Invest Ophthalmol Vis Sci 30, 323–329PubMedGoogle Scholar
  16. 16.
    Kosiewicz, M. M., Okamoto, S., Miki, S., Ksander, B. R., Shimizu, T., and Streilein, J. W. (1994) Imposing deviant immunity on the presensitized state. J Immunol 153, 2962–2973PubMedGoogle Scholar
  17. 17.
    Wilbanks, G. A., and 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, 383–389PubMedGoogle Scholar
  18. 18.
    Saban, D. R., Cornelius, J., Masli, S., Schwartzkopff, J., Doyle, M., Chauhan, S. K., Peck, A. B., and Grant, M. B. (2008) The role of ACAID and CD4+CD25+ FOXP3+ regulatory T cells on CTL function against MHC alloantigens. Mol Vis 14, 2435–2442PubMedGoogle Scholar
  19. 19.
    Zhang, H., Yang, P., Zhou, H., Meng, Q., and Huang, X. (2008) Involvement of Foxp3-expressing CD4+ CD25+ regulatory T cells in the development of tolerance induced by transforming growth factor-beta2-treated antigen-presenting cells. Immunology 124, 304–314PubMedCrossRefGoogle Scholar
  20. 20.
    Wilbanks, G. A., and Streilein, J. W. (1992) Macrophages capable of inducing anterior chamber associated immune deviation demonstrate spleen-seeking migratory properties. Reg Immunol 4, 130–137PubMedGoogle Scholar
  21. 21.
    Faunce, D. E., Sonoda, K. H., and Stein-Streilein, J. (2001) MIP-2 recruits NKT cells to the spleen during tolerance induction. J Immunol 166, 313–321PubMedGoogle Scholar
  22. 22.
    Kaplan, H. J., and Streilein, J. W. (1974) Do immunologically privileged sites require a functioning spleen? Nature 251, 553–554PubMedCrossRefGoogle Scholar
  23. 23.
    Weigle, W. O. (1973) Immunological unresponsiveness. Adv Immunol 16, 61–122PubMedCrossRefGoogle Scholar
  24. 24.
    Liblau, R. S., Tisch, R., Shokat, K., Yang, X., Dumont, N., Goodnow, C. C., and McDevitt, H. O. (1996) Intravenous injection of soluble antigen induces thymic and peripheral T-cells apoptosis. Proc Natl Acad Sci USA 93, 3031–3036PubMedCrossRefGoogle Scholar
  25. 25.
    Williamson, J. S., Bradley, D., and Streilein, J. W. (1989) Immunoregulatory properties of bone marrow-derived cells in the iris and ciliary body. Immunology 67, 96–102PubMedGoogle Scholar
  26. 26.
    Wilbanks, G. A., Mammolenti, M., and Streilein, J. W. (1992) Studies on the induction of anterior chamber-associated immune deviation (ACAID). III. Induction of ACAID depends upon intraocular transforming growth factor-beta. Eur J Immunol 22, 165–173PubMedCrossRefGoogle Scholar
  27. 27.
    Takeuchi, M., Kosiewicz, M. M., Alard, P., and Streilein, J. W. (1997) On the mechanisms by which transforming growth factor-beta 2 alters antigen-presenting abilities of macrophages on T cell activation. Eur J Immunol 27, 1648–1656PubMedCrossRefGoogle Scholar
  28. 28.
    D’Orazio, T. J., and Niederkorn, J. Y. (1998) A novel role for TGF-beta and IL-10 in the induction of immune privilege. J Immunol 160, 2089–2098PubMedGoogle Scholar
  29. 29.
    Takeuchi, M., Alard, P., and Streilein, J. W. (1998) TGF-beta promotes immune deviation by altering accessory signals of antigen-presenting cells. J Immunol 160, 1589–1597PubMedGoogle Scholar
  30. 30.
    Kosiewicz, M. M., Alard, P., and Streilein, J. W. (1998) Alterations in cytokine production following intraocular injection of soluble protein antigen: impairment in IFN-gamma and induction of TGF-beta and IL-4 production. J Immunol 161, 5382–5390PubMedGoogle Scholar
  31. 31.
    Kezuka, T., and Streilein, J. W. (2000) Analysis of in vivo regulatory properties of T cells activated in vitro by TGFbeta2-treated antigen presenting cells. Invest Ophthalmol Vis Sci 41, 1410–1421PubMedGoogle Scholar
  32. 32.
    Hecker, K. H., Niizeki, H., and Streilein, J. W. (1999) Distinct roles for transforming growth factor-beta2 and tumour necrosis factor-alpha in immune deviation elicited by hapten-derivatized antigen-presenting cells. Immunology 96, 372–380PubMedCrossRefGoogle Scholar
  33. 33.
    Masli, S., Turpie, B., and Streilein, J. W. (2006) Thrombospondin orchestrates the tolerance-promoting properties of TGFbeta-treated antigen-presenting cells. Int Immunol 18, 689–699PubMedCrossRefGoogle Scholar
  34. 34.
    Masli, S., and Turpie, B. (2009) Anti-inflammatory effects of tumour necrosis factor (TNF)-alpha are mediated via TNF-R2 (p75) in tolerogenic transforming growth factor-beta-treated antigen-presenting cells. Immunology 127, 62–72PubMedCrossRefGoogle Scholar
  35. 35.
    Ghafoori, P., Yoshimura, T., Turpie, B., and Masli, S. (2009) Increased IkappaB alpha expression is essential for the tolerogenic property of TGF-beta-exposed APCs. FASEB J 23, 2226–2234PubMedCrossRefGoogle Scholar
  36. 36.
    Zamiri, P., Masli, S., Kitaichi, N., Taylor, A. W., and Streilein, J. W. (2005) Thrombospondin plays a vital role in the immune privilege of the eye. Invest Ophthalmol Vis Sci 46, 908–919PubMedCrossRefGoogle Scholar
  37. 37.
    Li, Z., He, L., Wilson, K., and Roberts, D. (2001) Thrombospondin-1 inhibits TCR-mediated T lymphocyte early activation. J Immunol 166, 2427–2436PubMedGoogle Scholar
  38. 38.
    Van, V. Q., Darwiche, J., Raymond, M., Lesage, S., Bouguermouh, S., Rubio, M., and Sarfati, M. (2008) Cutting edge: CD47 controls the in vivo proliferation and homeostasis of peripheral CD4+ CD25+ Foxp3+ regulatory T cells that express CD103. J Immunol 181, 5204–5208PubMedGoogle Scholar
  39. 39.
    Grimbert, P., Bouguermouh, S., Baba, N., Nakajima, T., Allakhverdi, Z., Braun, D., Saito, H., Rubio, M., Delespesse, G., and Sarfati, M. (2006) Thrombospondin/CD47 interaction: a pathway to generate regulatory T cells from human CD4+ CD25- T cells in response to inflammation. J Immunol 177, 3534–3541PubMedGoogle Scholar
  40. 40.
    Avice, M. N., Rubio, M., Sergerie, M., Delespesse, G., and Sarfati, M. (2000) CD47 ligation selectively inhibits the development of human naive T cells into Th1 effectors. J Immunol 165, 4624–4631PubMedGoogle Scholar
  41. 41.
    Streilein, J. W., Bradley, D., Sano, Y., and Sonoda, Y. (1996) Immunosuppressive properties of tissues obtained from eyes with experimentally manipulated corneas. Invest Ophthalmol Vis Sci 37, 413–424PubMedGoogle Scholar
  42. 42.
    Vega, J. L., Keino, H., and Masli, S. (2009) Surgical denervation of ocular sympathetic afferents decreases local transforming growth factor-beta and abolishes immune privilege. Am J Pathol 175, 1218–1225PubMedCrossRefGoogle Scholar
  43. 43.
    Taylor, A. W., and Yee, D. G. (2003) Somatostatin is an immunosuppressive factor in aqueous humor. Invest Ophthalmol Vis Sci 44, 2644–2649PubMedCrossRefGoogle Scholar
  44. 44.
    Taylor, A. W., Streilein, J. W., and Cousins, S. W. (1994) Immunoreactive vasoactive intestinal peptide contributes to the immunosuppressive activity of normal aqueous humor. J Immunol 153, 1080–1086PubMedGoogle Scholar
  45. 45.
    Taylor, A., and Namba, K. (2001) In vitro induction of CD25+ CD4+ regulatory T cells by the neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH). Immunol Cell Biol 79, 358–367PubMedCrossRefGoogle Scholar
  46. 46.
    Taylor, A. W., Yee, D. G., and Streilein, J. W. (1998) Suppression of nitric oxide generated by inflammatory macrophages by calcitonin gene-related peptide in aqueous humor. Invest Ophthalmol Vis Sci 39, 1372–1378PubMedGoogle Scholar

Copyright information

© Humana Press 2010

Authors and Affiliations

  1. 1.Department of Ophthalmology, Harvard Medical SchoolSchepens Eye Research InstituteBostonUSA
  2. 2.Department of Neurology, Columbia University Medical CenterColumbia University College of Physicians and SurgeonsNew YorkUSA

Personalised recommendations