The function of immunoproteasomes in cytokine production and autoimmune diseases

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The immunoproteasome is known for its role in antigen processing along the MHC class I pathway. Recently, we have observed that the immunoproteasome subunits LMP2, MECL-1 and LMP7 are required for normal expansion and survival of T cells in virus infected mice. This has led us to hypothesize that the inhibition of immunoproteasomes could be a means to dampen undesired T cell responses in autoimmune diseases. Indeed, an inhibitor of LMP7 could prevent disease symptoms in collagen induced arthritis and collagen antibody induced arthritis. LMP7 inhibition interfered with the production of proinflammatory cytokines TNFα, IL-6, and IL-23 and the differentiation of Th17 cells in vitro. Given that Th17 cells are involved in the etiology of several autoimmune diseases, we would like to test in mouse models of inflammatory bowel disease, multiple sclerosis, and diabetes whether LMP7 inhibilion or deletion can suppress these diseases in vivo. In order lo investigate how the immunoproteasome may be mechanistically involved in the control of cytokine production we will investigate how LMP7 and MECL-1 deficiency affects the transcriptome and proteome of proliferating mouse T cells. Transcription factors known to be involved in T cell differentiation of Th1 and Thl7 cells will be investigated with respect to their phosphorylation status and expression level in the presence and absence of LMP7 inhibitor. In particular we will investigate why the lL-6 dependent phosphorylation of STAT3 is suppressed in the presence of PR-957. With these experiments we investigate the central hypothesis that the immunoproteasome may selectively process or degrade a factor involved in Th17 differentiation.