PROJECT ABSTRACT The IL-6 signaling pathway is dysregulated in autoimmunity in part through increased expression of the membrane bound IL-6R (mbIL-6R). The central hypothesis for the proposed studies is that elevated mbIL-6R expression leads to altered T cell fate and function resulting in pathogenic autoreactive T cells due to changes in the magnitude and balance of STAT1 and STAT3 phosphorylation. The following three Specific Aims will address this hypothesis. Aim 1 studies will determine the regulation of mbIL-6R expression in T cells from type 1 diabetes (T1D), relapsing remitting multiple sclerosis (RRMS) and rheumatoid arthritis (RA) subjects at the genetic, transcriptional, translational and post-translation level, focusing on the contribution of the IL6RAsp358Ala variant and ADAM17 mediated shedding. Aim 2 studies will determine how increased mbIL-6R alters the magnitude and balance of STAT1 and STAT3 phosphorylation and how these changes influence the T cell response with respect to lineage commitment, homing and response to regulation. These studies will take advantage of a cohort of healthy subjects with genetically determined mbIL-6R expression levels. Aim 3 studies will determine the impact of elevated mbIL-6R expression on both total T cells and autoreactive T cells in T1D, RRMS and RA. The primary endpoints will be T cell lineage commitment, transcriptional profile, and response to regulation. This aim will also determine the effect of elevated mbIL-6R expression on the islet specific T cell response to tocilizumab in T1D. The studies proposed in this application are appropriate for the “High Priority Immunology Grant (R01)” mechanism as it is research investigating the immunological mechanisms of autoimmune disease pathogenesis using well-defined human cohorts, high resolution immunophenotyping and systems immunology. These studies will advance our understanding of how subtle alterations in IL-6 signaling, contribute to the development and potentiation of autoimmunity.