PROJECT SUMMARY: Uveitis is a complex set of diseases that together constitute ~15% of visual morbidity worldwide. For many patients, uveitis can be a chronic life-long disease for which therapies may manage painful inflammation, but do not provide a cure. For some with rheumatologic conditions, uveitis is also accompanied by diseases of the joint, skin, or gut. Thus there is an urgent, unmet need to define key mechanisms of uveitis because of its significant associated personal, social, and economic burdens. Innate immunity, as the first line of defense against microbial pathogens, is a response that must be tightly regulated to avoid excessive inflammation and tissue destruction. Such regulation is especially important in the eye, where multiple factors and processes act together to limit inflammation so as to preserve the delicate cells and tissues critical to vision. The body senses potentially pathogenic microbes in the environment via innate immune receptors, which are classified into distinct families such as Toll-like receptors (TLRs) or NOD-like receptors (NLRs). One NLR, Nod2, not only serves as an intracellular sensor of microbial and foreign motifs, but is causally linked to non-infectious granulomatous uveitis in Blau syndrome. Using a model of T cell-mediated uveitis, experimental autoimmune uveitis (EAU), an unexpected novel role was identified for Nod2 in protection against autoimmune uveitis. Such protection was found to be conferred by CD4+ T cells and involved Nod2 modulation of the pathogenic capacity of a subset of CD4+ T cells, Th17 cells, by controlling their production of the cytokine IL-17. Based on these findings, as well as additional key preliminary data, this proposal aims to systematically probe the spectrum of actions by which Nod2 could impact the evolution of disease-causing T cells responses. Using methodologies that encompass molecular, cellular, and whole animal evaluation, experiments will test the central hypothesis that Nod2 is a critical immunomodulator of autoreactive T cells that cause uveitis, and are organized in three Specific Aims: 1) Delve into how Nod2 alters the uveitogenic potential of individual or populations of CD4+ T cells; 2) Elucidate the effects of Nod2 on the internal operations of T cells that intersect with T-cell receptor (TCR) signaling and T cell function; and 3) Determine whether Nod2 influences T cell development and maturation of uveitogenic T cells. The role of Nod2 in autoimmune diseases is an area that has yet to be more fully clarified. This research could potentially open up new avenues of investigation that could ultimately result in novel strategies for therapeutic intervention of uveitis, as well as of other vision-threatening diseases.