Immunobiology of EAU Recovery Through the Melanocortin-Adenosinergic Pathway

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Abstract Autoimmune uveitis is a debilitating and potentially blinding inflammatory disease that affects 93 in 100,000 Americans annually. The current treatment strategy is to control the inflammation with immunosuppressive medication that include steroids, which in turn have serious side effects, such as cataracts, glaucoma, peptic ulcers, bone decalcification, and systemic susceptibility to infection. A mouse model of human autoimmune uveitis, experimental autoimmune uveitis (EAU) has been used to better understand this disease. In contrast to chronic human uveitis, EAU resolves without intervention and mice are resistant to recrudescence of uveitis because of regulatory immunity found in the spleen. This regulatory immunity requires post-EAU Treg cells to be activated by post-EAU antigen presenting cells (APC). We have shown that the melanocortin 5 receptor (MC5r) is required for the emergence of a regulatory APC in the post- EAU spleen, and this regulatory APC is a source of adenosine that activates the post-EAU Treg cell through the adenosine 2A receptor (A2Ar). This is an interesting finding, because these two pathways have been shown to individually regulate immunity, but our observation is the first to link the two pathways. The result of stimulating this melanocortin-adenosinergic pathway is an autoantigen specific Treg cell that suppresses EAU. We have observed A2Ar-dependent Tregs emerge in the eye at the onset of EAU, persist through resolution, and expand in an A2Ar-dependent manner following EAU-reimmunization. Therefore, how these A2Ar- dependent ocular resident Tregs prevent relapse and the mechanism of A2Ar dependency will be answered (Aim 1). We have identified distinct A2Ar-dependent T cell Immunoglobulin and ITIM (TIGIT) TIGIT+ and PD-1+ post-EAU Treg subsets in the spleen. How these distinct Treg subsets are induced, how they suppress EAU, and if each subset has a different activation requirement in uveitis patients will be investigated (Aim 2). The post-EAU Treg cells express CCR7 that homes to secondary lymphoid tissue and CCR6 that homes to the eye, these Tregs are found in both tissue sites when reactivated, and expression of CCR6 and CCR7 induced through stimulation of the adenosinergic-melanocortin pathway on PBMC from uveitis patients is significantly reduced compared to healthy controls. Where and how the adenosinergic-melanocortin induced post-EAU Treg cells home to suppress uveitis will be investigated (Aim 3). Our hypothesis is that the melanocortin- adenosinergic pathway induces effective and long-term regulatory immunity that provides resistance to autoimmune uveitis. We propose to combine murine studies with translational studies to answer important mechanistic questions about ocular autoantigen specific Treg cells with the long-term goal of bringing these findings into the clinic to develop a uveitis treatment that provides lasting remission.