Local Control and Regulation of Retinal Autoimmunity

Project Summary/Abstract The balance and function of effector T cells, regulatory T cells, and anergic T cells are critical for maintaining immune homeostasis. Lack of regulatory T cells (Tregs) leads to autoimmunity mediated by self-antigen specific effector T cells whose targets can include tissues of the eye. Although most Tregs originate in the thymus, our previous studies suggest that in response to retinal self-antigens, Tregs can be generated locally in the retina from conventional CD4+ T cells, a process we refer to as "on-demand" Treg generation. T cell recognition of antigen-MHC-II complexes in the absence of costimulatory signals or in the presence of inhibitory signals can induce anergy, a state of functional unresponsiveness and non-proliferation in T cells. Thus, generation of anergic T cells may be another important mechanism for maintaining retinal immune homeostasis. We have observed a small number of T cells and a population of myeloid cells (microglia), a subset of which can act as conventional dendritic cells within the retina. Thus, we hypothesize there is a local, continual generation of retinal self-antigen specific Tregs and anergic T cells within the retina that contributes to retinal immune homeostasis and that the interaction between T cells, retinal microglia, and possibly non- myeloid retinal cells determines the nature and fate of retinal T cells. This hypothesis will be explored in three aims using the R161H mouse model of spontaneous retinal autoimmunity in conjunction with transgenic mice that allow for the tracking and depletion of dendritic cells, microglia, and Tregs. Aim 1: This aim will define the role that retinal microglia, particularly the dendritic cell subset, plays in antigen presentation that leads to autoimmune pathogenesis in the retina. Aim 2: This aim will define and distinguish the roles that resident retinal microglia versus the non-myeloid retinal cells play in production of anergic and regulatory T cells within the retina. Aim 3: This aim will be translational studies using local therapeutic manipulation of retinal microglia or other antigen presenting cells to limit T cell co-stimulation and promote generation of anergic and regulatory T cells to limit inflammatory injury to the retina.