Molecular Triggers of T Helper Lineage Choice

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Differentiation of thymocytes into alternate T killer and helper lineages is of great interest, due to its importance in shaping the T cell compartment and as a paradigm of binary lineage decisions. A growing consensus exists that lineage choice is determined instructively by differences in T cell receptor (TCR) signalling, although the molecular basis remains poorly understood. Recently, the transcription factor Zbtb7b has been identified as a "master regulator" of lineage choice, whose expression is necessary and sufficient to trigger the T helper fate. In this application, we propose to elucidate the mechanism by which TCR signaling controls lineage choice, by addressing the following questions: 1. How is repression of Zbtb7b transcription at the DP stage controlled? DP thymocytes do not express Zbtb7b, even when subjected to antibody-mediated TCR crosslinking. We will determine whether silencing of the Zbtb7b locus in DP thymocytes, as well as thymocytes undergoing commitment to the T killer lineage, is determined epigenetically or by repressive transcription factors. 2. What is the role of Ptprk in CD4 lineage commitment? T helper lineage development is specifically blocked in rats lacking the receptor Tyr phosphatase Ptprk, suggesting an essential role in mediating class II-restricted TCR signals. We will generate Ptprk-/- mice to test if Ptprk mediates a similar function in mice, and if so whether it affects CD4 lineage commitment directly. These experiments should provide insights into the molecular basis of alternate TCR signaling and the mechanism of lineage commitment.