Adaptive and innate regulation of immune privilege

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DESCRIPTION (provided by applicant): Systemic immunity to anterior chamber antigens is deviant; certain immune effectors (delayed hypersensitivity, Th2 responses, complement fixing antibodies) are deleted/suppressed, whereas others (cytotoxic T cells, non-complement fixing antibodies) are promoted. Anterior Chamber Associated Immune Deviation (ACAID) is an important expression of ocular immune privilege. During previous funding periods, our ACAID studies (i) showed that induction of ACAID CD8+ and ACAID CD4+ CD25- Tregs occurs in the marginal zone of the spleen rather than the white pulp while the generation of ACAID CD4+ CD25+ Treg does not; (ii) defined the genes associated with ACAID CD8+ Treg cells and showed that CD103, FoxP3 and MMP9 are necessary for ACAID efferent suppression. Based on these results, we propose an experimental plan for the next five years with the following three aims: (i) Compare and contrast ACAID CD4+ regulatory T cell subpopulations in regards to their mechanisms of suppression. (ii) Determine the mechanisms used by ACAID CD8+ Treg to suppress of CD4+ T effector cells, focusing on particular mechanisms used by CD8+ Treg derived - MMP9 and - retinoic acid receptor; (iii) test the significance of our findings for human immunology by studying ACAID Treg cells in a human chimera mouse model for ACAID. Our long-term goal is to push our understanding of ACAID and ocular immune privilege to the molecular level, and then to devise treatment strategies of very limited (or no) toxicity that prevent or suppress ocular inflammatory diseases (uveitis), or (ii) alleviate multifactorial eye diseases. PUBLIC HEALTH RELEVANCE: Understanding the basis for immunity within the eye, as well as appreciating the nature of immune responses to eye-derived antigens and pathogens are of considerable importance to other tissues as well as the eye. The studies will add new information to the field of T cell regulation in the eye and the periphery.