This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The T cell repertoire must be sufficiently diverse so that every pathogen we might encounter can be recognized and targeted for destruction. This great diversity must be regulated so that T cells do not recognize and destroy our own tissues and cause autoimmune diseases. The balance between broad immunologic diversity and restriction of the T cell repertoire to avoid autoimmunity is struck during the processes of positive and negative selection. When developing T cells first express a mature T cell receptor (TCR) complex, the cells are tested for their ability to recognize self-MHC complexes. Thymocytes expressing a TCR that binds MHC with high affinity undergo apoptosis via negative selection. Conversely, T cells that are unable to bind MHC undergo apoptosis via """"""""death-by-neglect"""""""". Only T cells expressing a TCR that can bind MHC with moderate affinity are positively selected and continue to mature. The goal of this research project is to understand how TCR-proximal signaling events regulate downstream signaling pathways. We hypothesize that the Gads adaptor protein regulates the signaling threshold through the TCR. This hypothesis is based on previous observations showing that Gads-deficient mice have defects in positive and negative selection. Despite these defects, Gads-/- mice can generate mature T cells, indicating that Gads is not required for TCR-mediated signaling. To test our hypothesis, we will identify the Gads-dependent signaling pathways that are required for positive and negative selection. Then, we will determine how Gads regulates the signaling threshold through the TCR and, in turn, regulates the downstream signaling pathways.
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