T Helper Cell Fate Specified by Kinase-Mediated Interaction of T-bet with GATA-3

Cell lineage specification depends on both gene activation and gene silencing, and in the differentiation of T helper progenitors to Th1 or Th2 effector cells, this requires the action of two opposing transcription factors, T-bet and GATA-3. T-bet is essential for the development of Th1 cells, and GATA-3 performs an equivalent role in Th2 development. We report that T-bet represses Th2 lineage commitment through tyrosine kinase–mediated interaction between the two transcription factors that interferes with the binding of GATA-3 to its target DNA. These results provide a novel function for tyrosine phosphorylation of a transcription factor in specifying alternate fates of a common progenitor cell.

[1]  L. Chodosh,et al.  Hlx is induced by and genetically interacts with T-bet to promote heritable TH1 gene induction , 2002, Nature Immunology.

[2]  S. Szabo,et al.  Molecular mechanisms regulating Th1 immune responses. , 2003, Annual review of immunology.

[3]  L. Atherly,et al.  The role of Tec family kinases in T cell development and function , 2003, Immunological reviews.

[4]  M. Yaffe,et al.  Biochemical Interactions Integrating Itk with the T Cell Receptor-initiated Signaling Cascade* , 2000, The Journal of Biological Chemistry.

[5]  I. Talianidis,et al.  Recruitment of hepatocyte nuclear factor 4 into specific intranuclear compartments depends on tyrosine phosphorylation that affects its DNA-binding and transactivation potential. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[6]  A. August,et al.  Attenuation of Immunological Symptoms of Allergic Asthma in Mice Lacking the Tyrosine Kinase ITK1 , 2003, The Journal of Immunology.

[7]  A. Sher,et al.  Mutation of Tec family kinases alters T helper cell differentiation , 2001, Nature Immunology.

[8]  S. Szabo,et al.  Development of Spontaneous Airway Changes Consistent with Human Asthma in Mice Lacking T-bet , 2002, Science.

[9]  A. Roy,et al.  Regulation of TFII-I Activity by Phosphorylation* , 1998, The Journal of Biological Chemistry.

[10]  R. Coffman,et al.  Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4+ T cells. , 1999, Immunity.

[11]  H. Varmus,et al.  Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity. , 1999, Science.

[12]  M. Reth,et al.  Interaction of SLP adaptors with the SH2 domain of Tec family kinases , 1999, European journal of immunology.

[13]  J. Drouin,et al.  Tpit determines alternate fates during pituitary cell differentiation. , 2003, Genes & development.

[14]  M. Yaffe,et al.  A motif-based profile scanning approach for genome-wide prediction of signaling pathways , 2001, Nature Biotechnology.

[15]  Laurie H Glimcher,et al.  A Novel Transcription Factor, T-bet, Directs Th1 Lineage Commitment , 2000, Cell.

[16]  S. Szabo,et al.  Distinct Effects of T-bet in TH1 Lineage Commitment and IFN-γ Production in CD4 and CD8 T Cells , 2002, Science.

[17]  Ralph Scully,et al.  Dynamic Changes of BRCA1 Subnuclear Location and Phosphorylation State Are Initiated by DNA Damage , 1997, Cell.

[18]  S. Szabo,et al.  Antigen-driven effector CD8 T cell function regulated by T-bet , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  P. Schwartzberg,et al.  Beyond calcium: new signaling pathways for Tec family kinases. , 2002, Journal of cell science.

[20]  J. Debnath,et al.  Tec Family Kinases Modulate Thresholds for Thymocyte Development and Selection , 2000, The Journal of experimental medicine.