The multi-step development and selection of T cell progenitors produces a mature population finely tuned to the recognition of self-encoded MHC alleles. Congenital defects in this process can result in a variety of diseases spanning immunodeficiency states to hyperactivity and autoimmunity. We propose to expand knowledge of the selection steps in T cell development, by focusing on a critical component of receptor- mediated signaling, the extracellular signal-regulated kinase (Erk) pathway. Three different mouse mutants have been produced that enable us to: visualize activation of the pathway, selectively inhibit the pathway, or identify new downstream substrates involved in the process of T cell differentiation. In mice with GFP expressed under control of the Id3 locus, lymphocytes fluoresce upon activation of Erk and its alteration of transcription factors of the Ets family. In mice with a conditional Erk deficiency we can cause deletion of the locus by treatment with 4-hydroxytamoxifen. And, in mice with a site-directed point mutation in Erk2, we can utilize synthetic ATP analogs to directly label natural substrates. We will use these strains of mice to dissect the timing and strength of extracellular signals and how this information guides the process of selection and commitment. Our long-term goal is to exploit these tools to characterize novel pathways of cellular differentiation downstream of Erk.
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