REGULATION OF SELF ANTIGEN PRESENTATION BY MHC CLASS II

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MHC class II molecules on antigen presenting cells (APC) bind self and foreign peptides intracellularly and display them on the cell surface for recognition by antigen-specific CD4+T cells. Display of self peptides by MHC class II molecules figures importantly in both normal and abnormal functioning of the immune system. However, little is known about the nature and origin of these self peptides, or the normal cell types on which they are displayed in vivo. I have hypothesized that activation or stress of APC via inflammatory stimuli or viral infection will alter the density and diversity of self peptides displayed by APC, and lead to disruption of peripheral self tolerance. To facilitate the study of self antigen presentation, I have developed a unique panel of T cells specific for 12 distinct naturally processed class II-bound self peptides derived from either transmembrane or cytosolic proteins. To gain a better understanding of the mechanism by which APC display self peptides bound to MHC class II molecules, I have proposed 3 aims. In Aim 1, I will test the hypothesis that activation with cytokines, bacterial LPS or cellular stress changes the array of self peptide class II complexes displayed by normal ex vivo murine APC. Subsequently, changes in antigen presentation will be manipulated with inhibitors of intracellular pathways. In Aim 2, I will test the hypothesis that distinct self antigens are proteolytically degraded and loaded onto class II molecules in different parts of the endocytic pathway, as a function of their original cellular location. These studies will involve subcellular fractionation techniques. In Aim 3, I will test the hypothesis that in vivo viral infection leads to changes in the array of self peptides displayed by normal APC. I will use an in vivo model of murine skin infection by Herpes Simplex Virus that will allow comparison of both lymphoid and epidermal PAC. These studies will study the effects of inflammation and the pathogenesis of viral infection on the display of self peptides by normal ex vivo APC, and will provide a rationale for linkage between infectious agents and autoimmune T cell responses.