ITK: an emerging target for treatment of T cell-mediated autoimmune diseases Lymphocyte-mediated autoimmune diseases arise from a breakdown of self-tolerance. One of the key proteins regulating self-tolerance is the inhibitory T cell protein, CTLA-4. When CTLA-4 is absent, mice succumb to a rapid and fatal multi-organ autoimmune disease, and die by three weeks of age. Recent studies from our labs have demonstrated that CTLA-4 has two distinct functions in preventing autoimmunity. First, CTLA-4 is required for the function of FOXP3+ regulatory T cells in maintaining T cell tolerance. Second, CTLA-4 is required in conventional T cells, to block aberrantly activated self-reactive T cell accumulation in tissues under non-inflammatory conditions. It is unknown how costimulatory molecules control aberrantly activated self-reactive T cells from infiltrating and damaging tissues. Based on the observation that the null mutation of the Tec kinase Itk prevents activated T cell migration and autoimmune pathology of Ctla4-/- mice, we propose that ITK activation is critical for T cell-mediated autoimmune diseases. We hypothesize that ITK is required for the synergistic activation of VAV1 and the pathways downstream of VAV1 leading to actin polymerization and cytoskeletal reorganization. Further, we propose that ITK activates VAV1 by phosphorylating and activating the Src family kinase, FYN, which in turn phosphorylates and activates VAV1. We will test this hypothesis by examining the migratory behavior of self-reactive T cells from Itk-/- mice in vitro and in vivo to determine the molecular mechanism by which ITK controls T cell movement into non-lymphoid tissues. We will also determine whether ITK regulates cytoskeletal reorganization in primary T cells by activating FYN, whether FYN is required for actin polymerization and cytoskeletal reorganization in primary T cells and contribute to autoimmune disease progression. Finally, we will investigate the efficacy and mechanism of suppression of Type I diabetes in animals by small molecule inhibitors of ITK, to begin to explore the utility of targeted ITK blockade in clinics to treat various organ-specific autoimmune diseases.
ITK: an emerging target for treatment of T cell-mediated autoimmune diseases occur when an individual's immune system attacks his/her own cells and organs. This proposal addresses one of the basic mechanisms that prevent autoimmunity from occurring in healthy individuals. A better understanding of this mechanism may provide opportunities to prevent the onset of autoimmune processes in susceptible individuals and to treat and cure patients with these diseases.
|Cho, Hyoung-Soo; Shin, Hyun Mu; Haberstock-Debic, Helena et al. (2015) A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression. J Immunol 195:4822-31|
|Nayar, Ribhu; Schutten, Elizabeth; Bautista, Bianca et al. (2014) Graded levels of IRF4 regulate CD8+ T cell differentiation and expansion, but not attrition, in response to acute virus infection. J Immunol 192:5881-93|
|Yin, Catherine C; Cho, Ok Hyun; Sylvia, Katelyn E et al. (2013) The Tec kinase ITK regulates thymic expansion, emigration, and maturation of ?? NKT cells. J Immunol 190:2659-69|
|Jain, Nitya; Miu, Bing; Jiang, Jian-kang et al. (2013) CD28 and ITK signals regulate autoreactive T cell trafficking. Nat Med 19:1632-7|
|Joseph, Raji E; Kleino, Iivari; Wales, Thomas E et al. (2013) Activation loop dynamics determine the different catalytic efficiencies of B cell- and T cell-specific tec kinases. Sci Signal 6:ra76|
|Malhotra, Nidhi; Kang, Joonsoo (2013) SMAD regulatory networks construct a balanced immune system. Immunology 139:1-10|
|Nayar, Ribhu; Enos, Megan; Prince, Amanda et al. (2012) TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8+ T-cell differentiation. Proc Natl Acad Sci U S A 109:E2794-802|