NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression.

T helper (Th) 2 cells selectively express IL-21 in addition to the classic Th2 cytokines IL-4, IL-5, and IL-13. In contrast to these clustered Th2 cell cytokine genes, the IL-21 gene resides on a different chromosome and is not coordinately regulated by the same locus control region that directs the expression of other Th2 cytokines. We demonstrate that the proximal promoter of IL-21 controls its Th-cell-subset-specific expression through the action of NFATc2 and T-bet. Whereas NFATc2 directly binds to and activates transcription of the IL-21 promoter in Th2 cells, T-bet represses IL-21 transcription by inhibiting the binding of NFATc2 to the promoter in Th1 cells. These data suggest that there are multiple mechanisms by which Th-cell-subset-specific cytokine genes are regulated.

[1]  Ivan Ovcharenko,et al.  rVISTA 2.0: evolutionary analysis of transcription factor binding sites , 2004, Nucleic Acids Res..

[2]  A. Rao,et al.  A Distal Enhancer in the Interferon-γ (IFN-γ) Locus Revealed by Genome Sequence Comparison* , 2003, Journal of Biological Chemistry.

[3]  R. Flavell,et al.  Regulation of the Th2 cytokine locus by a locus control region. , 2003, Immunity.

[4]  A. Satoskar,et al.  Interleukin 21 Is a T Helper (Th) Cell 2 Cytokine that Specifically Inhibits the Differentiation of Naive Th Cells into Interferon γ–producing Th1 Cells , 2002, The Journal of experimental medicine.

[5]  Anjana Rao,et al.  NFAT1 and NFAT2 are positive regulators of IL‐4 gene transcription , 2002, European journal of immunology.

[6]  Anjana Rao,et al.  TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes , 2002, Nature Immunology.

[7]  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.

[8]  Michael Q. Zhang,et al.  Use of Chromatin Immunoprecipitation To Clone Novel E2F Target Promoters , 2001, Molecular and Cellular Biology.

[9]  Edward M. Rubin,et al.  Deletion of a coordinate regulator of type 2 cytokine expression in mice , 2001, Nature Immunology.

[10]  J. Sedat,et al.  Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. , 2001, Immunity.

[11]  Scott R. Presnell,et al.  Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function , 2000, Nature.

[12]  R. Locksley,et al.  Coordinate Regulation of the IL-4, IL-13, and IL-5 Cytokine Cluster in Th2 Clones Revealed by Allelic Expression Patterns1 , 2000, The Journal of Immunology.

[13]  A. Rao,et al.  Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo. , 2000, Immunity.

[14]  W. Miller,et al.  Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. , 2000, Science.

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

[16]  L. Glimcher,et al.  The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines. , 1999, Immunity.

[17]  L. Glimcher,et al.  c-maf Promotes T Helper Cell Type 2 (Th2) and Attenuates Th1 Differentiation by Both Interleukin 4–dependent and –independent Mechanisms , 1998, The Journal of experimental medicine.

[18]  M. Kaplan,et al.  Regulation of T helper cell differentiation by STAT molecules , 1998, Journal of leukocyte biology.

[19]  E. Serfling,et al.  NF-ATp plays a prominent role in the transcriptional induction of Th2-type lymphokines. , 1997, Immunology letters.

[20]  Richard A Flavell,et al.  The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells , 1997, Cell.

[21]  K. Frazer,et al.  Computational and biological analysis of 680 kb of DNA sequence from the human 5q31 cytokine gene cluster region. , 1997, Genome research.

[22]  R. Flavell,et al.  Reprogramming the signalling requirement for AP-1 (activator protein-1) activation during differentiation of precursor CD4+ T-cells into effector Th1 and Th2 cells. , 1997, Genes and function.

[23]  Laurie H Glimcher,et al.  The Proto-Oncogene c-maf Is Responsible for Tissue-Specific Expression of Interleukin-4 , 1996, Cell.

[24]  L. Glimcher,et al.  Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice. , 1996, Immunity.

[25]  J. W. Rooney,et al.  Coordinate and cooperative roles for NF-AT and AP-1 in the regulation of the murine IL-4 gene. , 1995, Immunity.

[26]  L. Glimcher,et al.  NFATc1 and NFATc2 together control both T and B cell activation and differentiation. , 2001, Immunity.

[27]  A Radbruch,et al.  Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. , 2000, Immunity.

[28]  T. Werner,et al.  MatInd and MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data. , 1995, Nucleic acids research.