Arthritis, a chronic immune-mediated disease involving painful destruction of the joints, presents a considerable medical challenge to our US Veteran population due to incomplete understanding of its pathogenesis. An emerging paradigm proposes that self-reactive (or autoreactive) T cells influenced by genetic-environmental interactions initiate and perpetuate disease. Understanding how these factors contribute to generation of autoreactive T cells and their subsequent expansion and ability to cause disease is centrally important in determining the etiology of arthritis. This project aims to address this critical question in the field of autoimmunity by focusing on the relationships between autoreactive T cells, the epithelial cells within the thymus, and the innate immune receptor Nod2. T cell development and “education” occurs within the thymus, a primary lymphoid organ that serves a critical role in eliminating self-reactive T cells and preventing autoimmune disease. In the unfortunate event that autoreactive T cells leave the thymus and enter the periphery, they can become activated and differentiate into IL-17-secreting T cells (Th17 cells), a subset of cells known to cause arthritis. The proposed studies utilize a unique experimental mouse model of arthritis in SKG mice, which are genetically predisposed to produce autoreactive T cells (due to impaired selection within the thymus). We have expanded on the SKG model by genetically-modifying mice to also lack expression of Nod2, which has uncovered an entirely novel role for the innate immune receptor Nod2 in protection against of arthritis. This discovery bears clinical relevance to humans, as patients with mutations in NOD2 develop an inherited form of arthritis called Blau syndrome. Nod2 is a member of the cytosolic NOD-like receptor (NLR) family of innate immune receptors known to directly sense microbial, or foreign, motifs within the body. By understanding how Nod2 regulates autoreactive T cells in arthritis, we hope to better understand how extrinsic, or environmental, signals can contribute to clinical arthritis; thereby specifically investigating how a genetically determined shift of T cell-repertoire coupled with environmental stimuli facilitates the differentiation of autoreactive Th17 cells and drives disease. These findings, in both humans and rodents, underscore an essential homeostatic role for Nod2 in joint disease; the key observation we have made linking Nod2 specifically with control over T cell responses in arthritis, is the basis of this application. The goal of this application is two-fold: (1) To determine whether Nod2 influences development arthritogenic T cells within the thymus; and (2) To elucidate the immunoregulatory effects of Nod2 on peripheral activation of arthritogenic Th17 cells that cause arthritis. Experiments have been designed to examine T cell-intrinsic functions of Nod2 at the cellular and molecular level as well as in vivo functionality of peripheral v...