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).
| Buono, Chiara; Binder, Christoph J; Stavrakis, George et al. (2005) T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses. Proc Natl Acad Sci U S A 102:1596-601 |
| Dorfman, David M; Hwang, Eun Sook; Shahsafaei, Aliakbar et al. (2005) T-bet, a T cell-associated transcription factor, is expressed in Hodgkin's lymphoma. Hum Pathol 36:10-5 |
| Lord, Graham M; Rao, Ravi M; Choe, Hyeryun et al. (2005) T-bet is required for optimal proinflammatory CD4+ T-cell trafficking. Blood 106:3432-9 |
| Hwang, Eun Sook; Szabo, Susanne J; Schwartzberg, Pamela L et al. (2005) T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 307:430-3 |
| Townsend, Michael J; Weinmann, Amy S; Matsuda, Jennifer L et al. (2004) T-bet regulates the terminal maturation and homeostasis of NK and Valpha14i NKT cells. Immunity 20:477-94 |
| Peng, Stanford L; Townsend, Michael J; Hecht, Jonathan L et al. (2004) T-bet regulates metastasis rate in a murine model of primary prostate cancer. Cancer Res 64:452-5 |
| Dorfman, David M; Hwang, Eun Sook; Shahsafaei, Aliakbar et al. (2004) T-bet, a T-cell-associated transcription factor, is expressed in a subset of B-cell lymphoproliferative disorders. Am J Clin Pathol 122:292-7 |
| Bettelli, Estelle; Sullivan, Brandon; Szabo, Susanne J et al. (2004) Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J Exp Med 200:79-87 |
| Dorfman, David M; van den Elzen, Peter; Weng, Andrew P et al. (2003) Differential expression of T-bet, a T-box transcription factor required for Th1 T-cell development, in peripheral T-cell lymphomas. Am J Clin Pathol 120:866-73 |
| Sullivan, Brandon M; Juedes, Amy; Szabo, Susanne J et al. (2003) Antigen-driven effector CD8 T cell function regulated by T-bet. Proc Natl Acad Sci U S A 100:15818-23 |
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