During ongoing immune responses, naive helper T precursor (Thp) cells differentiate into one of two lineages, Th1 or Th2, characterized by the expression of particular cytokines. This polarity mediates the balance between disease pathogenesis and suppression in several human conditions, including allergy; autoimmunity, and infection; however, the molecular basis of Th1 development remains largely unknown. Recently, a novel protein, T-bet (T-box expressed in T cells), has been isolated and found highly selective for Th1 cells, though it is also found in thymocytes, as well as NK and B cells. Interestingly, T-bet is a member of the T-box family of transcription factors, which have largely been implicated in embryonic development. Expression of this protein is sufficient to confer the Th1 phenotype upon both Thp and polarized Th2 cells, suggesting that it plays a substantial role in Th lineage commitment: This application proposes to analyze the biological function of T-bet by developing T-bet genetic mutant mice (Aim 1), identifying regulators and effectors of T-bet (Aim 2), and understanding its potential role in disease states (Aim 3).
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