EXCEED THE SPACE PROVIDED. It has been apparent for some time, based upon work by others and upon studies performed during an earlier funding cycle of this grant, that T cells and the cytokines they produce are necessary for complete disease penetrance in murine models of SLE. Nevertheless, it had not been clear that the T cell abnormalities in lupus were intrinsic, versus secondary to other immune irregularities in disease, for example, exuberant APC or B cell activation with subsequent activation and recruitment of T cell help, nor had it been clear what, if any, the intrinsic T cell abnormalities might be. Work done during the current funding cycle has defined for the first time that one of the forces driving activation of CD4+ T cells in lupus is an intrinsically (genetically) heightened response to self-peptide-MHC complexes, particularly those that bind the TCP with low affinity, events that are associated with a proximal defect in TCR-CD3 mediated signal transduction, and are also associated with anergy avoidance in vivo. These events lead to peripheral tolerance loss, despite production of suppressive cytokines and despite activation of regulatory T cells. Additional studies done during this funding cycle have shown that in normal mice tolerance mechanisms that control T cell responses to such low affinity self-ligands, even in the setting of enhanced costimulation, are intact; however, these mechanisms are abrogated in lupus, and this abrogation is due to an intrinsic T cell defect. The overall goals of this work, submitted as an extension of R37AR40072, are to further define the pathway(s) that accounts for the hyper-responsiveness of CD4+ T cells from lupus-prone mice following TCR engagement, seeking the biochemical and genetic basis for this phenotype. PERFORMANCE SITE ========================================Section End===========================================

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Gretz, Elizabeth
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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