GENE REGULATION IN T HELPER 1 CELLS

Harvard University (Sch Of Public Hlth), Boston MA

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Abstract

Upon stimulation with antigen, the naive T helper precursor (Thp) cell undergoes changes in gene expression that ultimately propel it down a Th1 or Th2 lineage. Over the last few years, significant progress has been made in identifying the transcription factors that control the transition of a Thp to a Th2 cells, but very little is known about the molecular basis of Th1 differentiation. Thus, we cannot reconstitute the expression of IFN- gamma in a non-producer cell as we can do for IL-4 with c-maf. In this renewal application we propose to study in detail a new transcription factor we have recently isolated using a combination of RDA and a yeast one-hybrid screen. This factor is a new member of the T box family of transcription factors whose founding member is the brachyury gene. We have named it T-bet (T box expressed in T cells) since it is expressed selectively in thymocytes and in Th1 cells. Within the thymus, it is expressed at highest levels in DN and Rag2-/- thymocytes. In Th1 cells, T-bets's expression is inducible both by TcR-mediated signals and by IL- 12. Of interest, T-bet is one of a very small number of transcription factors (e.g. the Stats) to be tyrosine phosphorylated. Further, retroviral transduction of T-bet represses the production of Il-4 in a Tho hybrid. These data suggest that T-beta plays an important role in controlling T helper lineage commitment, but much remains to be learned about the expression, regulation and function of T-bet. We propose to perform structure function and expression analysis of T-bet to identify the stimuli that induce tyrosine (Aim 1), establish the function of T-bet in vivo both by creating T-bet genetic mutant mice (Aim 1), establish the function of T-bet in vivo both by creating T-bet genetic mutant mice (Aim 2) and by identifying T-bet target genes (Aim 3) and understand the signal transduction pathways upstream and downstream of T-bet by isolating T- bet interacting proteins (Aim 4).