Development of autoimmune diseases is a result of breakdown of self-tolerance in the thymus and/or changes in the activation thresholds of peripheral lymphocytes. Recent genetic studies on Cbl-b gene-targeted mice showed that Cbl-b deficiency changes the signaling thresholds: Cbl-b deficiency uncouples T cell proliferation, IL-2 production from the co-stimulation of CD28; the gene-targeted mice develop spontaneous autoimmunity or become highly susceptible to exogenous antigen-induced autoimmune diseases. These studies suggest a critical role of Cbl-b in the regulation of T cell activation thresholds and hence in the maintenance of the balance between immunity and tolerance. Our recent demonstration that the RING finger of Cbl, a Cbl-b homologue, can recruit and activate ubiquitin (Ub) conjugation enzyme (Ubc), and that Cbl then facilitates Ub conjugation to the protein tyrosine kinases it associates with, may suggest that Cbl-b could also function as a Ub ligase for Cbl-b-binding proteins. However, the target proteins for Cbl-b-mediated ubiquitination and the link to the induction of autoimmune responses are far from clear. Considering the recent progress on the understanding of Cbl family proteins and on the recent biochemical and genetic data on Cbl-b, we propose the following model regarding the biological function of Cbl-b in T cells: Cbl-b, as both an adaptor protein and a Ub ligase, recruits Ub-loaded Ubc through its RING finger. Cbl-b then helps tag Ub to protein substrates, through a specific interaction of Cbl-b protein interaction domains with its binding partners. Ubiquitination of these target proteins may lead to their downregulation and/or their biological function. Cbl-b-induced ubiquitination events may then change the thresholds of T cells in response to the stimulation of TCR and CD28, which eventually causes the induction and expansion of autoreactive T cells for the subsequent development of autoimmune diseases. We will test this hypothesis by the identification and the functional analysis of intracellular targets for Cbl-b, and as a part of future plan, by the establishment and functional analysis of Cbl-b deficient mice model of autoimmune diabetes. The information generated by the proposed studies will enhance our understanding of the biological function of Cbl-b in physiological T cell tolerance and in pathological autoreactive T cell responses, and will shed light on the development of novel therapeutic approaches to autoimmune diabetes.
|Liu, Yun-Cai (2004) Ubiquitin ligases and the immune response. Annu Rev Immunol 22:81-127|
|Heissmeyer, Vigo; Macian, Fernando; Im, Sin-Hyeog et al. (2004) Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat Immunol 5:255-65|
|Jeon, Myung-Shin; Atfield, Alex; Venuprasad, K et al. (2004) Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity 21:167-77|
|Zhang, Wenying; Shao, Yuan; Fang, Deyu et al. (2003) Negative regulation of T cell antigen receptor-mediated Crk-L-C3G signaling and cell adhesion by Cbl-b. J Biol Chem 278:23978-83|