Recent evidence indicates that survival of naive peripheral T cells is an active process requiring the interaction of the T cell receptor with self-peptides presented by the same MHC molecules that are responsible for thymic selection. However this T cell receptor interaction with self MHC does not lead to T cell activation because this process is dampened by a family of negative regulators of activation. Recent work from our group indicates that faulty negative regulation may permit the activation of autoreactive T cells, and that intrinsic hyporesponsiveness of T cell receptor signaling in autoimmune prone animals may further enhance any deficiency in negative regulation. Together, these conditions can lead to enrichment of peripheral autoreactive T cells and ultimately instigate autoimmune disease. This application will reinforce a collaboration between two laboratories with expertise in cell cycle regulation and the immunbiology of Type I diabetes. The experiments proposed are designed to test the hypotheses that (1) failure of negative regulation leads to abortive cell cycle entry and death unless the T cells receive a strong survival signal and (2) because of an intrinsic hyporesponsiveness in T cell receptor signaling the failure of negative regulation preferentially permits the expansion of autoreactive clones resulting in autoimmunity.
| May, Sarah L; Zhou, Qing; Lewellen, Mitzi et al. (2014) Nfatc2 and Tob1 have non-overlapping function in T cell negative regulation and tumorigenesis. PLoS One 9:e100629 |
| Jubala, Cristan M; Lamerato-Kozicki, Angela R; Borakove, Michelle et al. (2009) MHC-dependent desensitization of intrinsic anti-self reactivity. Cancer Immunol Immunother 58:171-85 |
| Modiano, Jaime F; Johnson, Lisa D S; Bellgrau, Donald (2008) Negative regulators in homeostasis of naive peripheral T cells. Immunol Res 41:137-53 |
| Modiano, Jaime F; Sun, Juan; Lang, Julie et al. (2004) Fas ligand-dependent suppression of autoimmunity via recruitment and subsequent termination of activated T cells. Clin Immunol 112:54-65 |
