Antigen presention by glial cells in stimulating T cells

Cleveland Clinic Lerner Com-Cwru, Cleveland OH

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Abstract

T cell mediated immune responses within the central newous system (CNS) are beneficial by clearing infectious agents, but are also detrimental by activating resident cells and destroying tissue, leading to immunopathogy. A vital force in triggering T cell effector function both during virus and auto-Ag induced inflammation is recognition of cognate antigen (Ag) presented by major histocompatibility antigens (MHC) within the CNS. Strict regulation of MHC expression within the CNS is thus a critical determinant in disease progression. This proposal examines MHC dependent T cell regulation during acute and persistent viral infection established by the neurotropic JHM virus, a member of the coronaviridae. Despite control of acute infection by T cells, the consequences are ongoing chronic demyelination associated with virus persistence in the form of noninfectious RNA. The tropism of this virus for a variety of CNS cell types provides a unique model to analyze the contribution of individual glial cells to Ag presentation and T cell stimulation. Our overall hypothesis is that interactions with distinct glial cell populations result in heterologous outcomes with respect to CD8 + T cell activation, suwival and pathogenesis. Aim 1 examines the role of type I versus type II interferons in inducing MHC class I and class II expression on glial cell subsets during acute virus infection in vivo. Aim 2 tests the hypothesis that class I/CD8+ T cell interactions are critical in augmenting class II expression on microglia via secretion of IFN-gamma. This is based on the observation that class I expression precedes class II expression on resident CNS cells. Aim 3 evaluates the ability of glial cell subsets to stimulate CD8+ T cells during acute infection. Relative Ag presentation capacities of oligodendrocytes, astrocytes and microglia during distinct stages of inflammation will be assessed using highly sensitive virus specific T cell hybridomas in and T cell transfers in vivo. Aim 4 addresses the correlation between viral persistence, Ag presentation, and IFN-gamma/RANTES secretion in mediating retention of T cells within the CNS. Transgenic technology, specifically mice expressing green fluorescent protein (GFP) in distinct glial cells, and flow cytometry will be used to characterize interactions between T cells and distinct glial cells in vivo. The goals of this proposal are to delineate contributions of individual glial cell types in regulating CD8+ and CD4+ T cells in a MHC-dependent manner. Specifically the propensity of oligodendrocytes and astrocytes to interact with CD8+ T cells in an Ag specific manner in vivo will be revealed. Lastly, the mechanisms regulating T cell secretion of cytokine/chemokine during persistence, thus potentially contributing to chronic demyelination, will be defined.