Schepens Eye Research Institute
20 Staniford Street
Boston, MA 2114
Our broad interest in regional and innate immunity is interpreted into four major projects: 1) Role of regional antigen presenting cells (APCs) in regulation of immune outcome; 2) Role of NKT cells in induction of anterior chamber associated immune deviations (ACAID) and generation of peripheral tolerance 3) Interactions of NKT cells and eye derived APCs within cell clusters in the marginal zone of the spleen 4) Chemokines, NKT cells and tolerance induced through immune privilege sites.
ACAID is an ocular form of immune deviation that is based on tolerance inducing signals that leave the antigen inoculated eye (anterior chamber) and travel through the blood to the marginal zone of the spleen where immune deviation and antigen specific T regulatory (Tr) cells develop. ACAID occurs if the delayed type hypersensitivity (DTH) response (ear swelling) to the immunizing antigen is suppressed and the isotype of the antigen specific immunoglobulin does not fix complement (IgG1 and IgE) in contrast to immunoglobulin isotypes associated with DTH that fix complement (IgG2a). NKT cell deficient mice (CD1-/-, ja281-/-) do not develop ACAID unless reconstituted with NKT cells. Current research investigates the mechanisms of NKT cells and eye derived APC interactions that lead to the generation of antigen specific Tr cells and peripheral tolerance. In vitro approaches allow us to dissect the interactions of the APCs with NKT cells. We observe that the interaction of NKT cells with CD1 on APCs induces the synthesis of immunosuppressive cytokines and chemokines that influence the development of cell clusters in the marginal zone of the spleen and the ultimate generation of T regulatory cells that regulate the effector arm of both Th1 and Th2 immune responses. The study of tolerance inducing mechanisms of the eye may lead to novel approaches for treatment of autoimmune disease in the eye and other organs.
SWatté CM, Nakamura T, Lau CH, Ortaldo JR, Stein-Streilein J. Ly49 C/I dependent NKT cell derived IL-10 is required for corneal graft survival and peripheral tolerance. J Leukoc Biol 2008;83:928-935.
Sonoda KH, Nakamura T, Young HA, Hart D, Carmeliets P, Stein-Streilein, J. NKT cell-derived urokinase-type plasminogen activator promoted peripheral tolerance associated with eye. J Immunol 2007;179:2215-2222.
Sugita S, Keino H, Futagami Y, Mochizuki M, Stein-Streilein J. Streilein JW. B7+ Iris Pigment Epithelial Cells Convert T Cells into CTLA-4+, B7-expressing CD8+ Regulatory T Cells. Invest Ophthalmol Vis Sci 2006;47:5376-5384.
Keino H, Takeuchi M, Kezuka T, Hattori T, Usui M, Taguchi O, Streilein JW, Stein-Streilein J. Induction of Eye-Derived Tolerance Does Not Depend on Naturally Occurring CD4+CD25+ T Regulatory Cells. Invest Ophthalmol Vis Sci 2006;47(3):1047-55.
Keino H, Masli S, Sasaki S, Streilein WJ, Stein-Streilein J. CD8+ T Regulatory Cells Use a Novel Genetic Program that Includes CD103 to Suppress Th1 Immunity in Eye-Derived Tolerance. Invest Ophthalmol Vis Sci 2006;47:1533-42.
Last Update: 1/6/2014