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GATA-3 controls the maintenance and proliferation of T cells downstream of TCR and cytokine signaling

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Abstract

GATA-3 controls T helper type 2 (TH2) differentiation. However, whether GATA-3 regulates the function of mature T cells beyond TH2 determination remains poorly understood. We found that signaling via the T cell antigen receptor (TCR) and cytokine stimulation promoted GATA-3 expression in CD8+ T cells, which controlled cell proliferation. Although GATA-3-deficient CD8+ T cells were generated, their peripheral maintenance was impaired, with lower expression of the receptor for interleukin 7 (IL-7R). GATA-3-deficient T cells had defective responses to viral infection and alloantigen. The proto-oncoprotein c-Myc was a critical target of GATA-3 in promoting T cell proliferation. Our study thus demonstrates an essential role for GATA-3 in controlling the maintenance and proliferation of T cells and provides insight into immunoregulation.

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Figure 1: GATA-3 expression in CD8+ T cells.
Figure 2: CD8+ T cell development in the absence of GATA-3.
Figure 3: Defective peripheral maintenance of GATA-3-deficient CD8+ T cells.
Figure 4: The function of activated CD8+ T cells requires GATA-3.
Figure 5: GATA-3 is important for the population expansion of activated CD8+ T cells in vivo.
Figure 6: GATA-3 controls c-Myc expression.

References

  1. Zhang, N. & Bevan, M.J. CD8+ T cells: foot soldiers of the immune system. Immunity 35, 161–168 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. Cantrell, D. T cell antigen receptor signal transduction pathways. Annu. Rev. Immunol. 14, 259–274 (1996).

    CAS  PubMed  Article  Google Scholar 

  3. Miyajima, A., Kitamura, T., Harada, N., Yokota, T. & Arai, K. Cytokine receptors and signal transduction. Annu. Rev. Immunol. 10, 295–331 (1992).

    CAS  PubMed  Article  Google Scholar 

  4. Zheng, W. & Flavell, R.A. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89, 587–596 (1997).

    CAS  Article  PubMed  Google Scholar 

  5. Zhu, J. et al. Conditional deletion of Gata3 shows its essential function in TH1-TH2 responses. Nat. Immunol. 5, 1157–1165 (2004).

    CAS  Article  PubMed  Google Scholar 

  6. Wang, L. et al. Distinct functions for the transcription factors GATA-3 and ThPOK during intrathymic differentiation of CD4+ T cells. Nat. Immunol. 9, 1122–1130 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Ting, C.N., Olson, M.C., Barton, K.P. & Leiden, J.M. Transcription factor GATA-3 is required for development of the T-cell lineage. Nature 384, 474–478 (1996).

    CAS  PubMed  Article  Google Scholar 

  8. Pai, S.Y. et al. Critical roles for transcription factor GATA-3 in thymocyte development. Immunity 19, 863–875 (2003).

    CAS  PubMed  Article  Google Scholar 

  9. Vosshenrich, C.A. et al. A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127. Nat. Immunol. 7, 1217–1224 (2006).

    CAS  PubMed  Article  Google Scholar 

  10. Samson, S.I. et al. GATA-3 promotes maturation, IFN-γ production, and liver-specific homing of NK cells. Immunity 19, 701–711 (2003).

    CAS  PubMed  Article  Google Scholar 

  11. Wang, Y., Su, M.A. & Wan, Y.Y. An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity 35, 337–348 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Wohlfert, E.A. et al. GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice. J. Clin. Invest. 121, 4503–4515 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Cipolletta, D. et al. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486, 549–553 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Hoyler, T. et al. The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity 37, 634–648 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Mjösberg, J. et al. The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity 37, 649–659 (2012).

    PubMed  Article  CAS  Google Scholar 

  16. Sanda, T. et al. Core transcriptional regulatory circuit controlled by the TAL1 complex in Human T cell acute lymphoblastic leukemia. Cancer Cell 22, 209–221 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. van Hamburg, J.P. et al. Cooperation of Gata3, c-Myc and Notch in malignant transformation of double positive thymocytes. Mol. Immunol. 45, 3085–3095 (2008).

    CAS  PubMed  Article  Google Scholar 

  18. Hernández-Hoyos, G., Anderson, M.K., Wang, C., Rothenberg, E.V. & Alberola-Ila, J. GATA-3 expression is controlled by TCR signals and regulates CD4/CD8 differentiation. Immunity 19, 83–94 (2003).

    PubMed  Article  Google Scholar 

  19. Guo, L. et al. IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells. Proc. Natl. Acad. Sci. USA 106, 13463–13468 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. Lee, P.P. et al. A Critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 15, 763–774 (2001).

    CAS  PubMed  Article  Google Scholar 

  21. Amsen, D. et al. Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch. Immunity 27, 89–99 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Kieper, W.C. & Jameson, S.C. Homeostatic expansion and phenotypic conversion of naive T cells in response to self peptide/MHC ligands. Proc. Natl. Acad. Sci. USA 96, 13306–13311 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. Goldrath, A.W. & Bevan, M.J. Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts. Immunity 11, 183–190 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Shapiro-Shelef, M., Lin, K.I., Savitsky, D., Liao, J. & Calame, K. Blimp-1 is required for maintenance of long-lived plasma cells in the bone marrow. J. Exp. Med. 202, 1471–1476 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Schluns, K.S., Kieper, W.C., Jameson, S.C. & Lefrancois, L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat. Immunol. 1, 426–432 (2000).

    CAS  PubMed  Article  Google Scholar 

  26. Yamashita, M. et al. Identification of a conserved GATA3 response element upstream proximal from the interleukin-13 gene locus. J. Biol. Chem. 277, 42399–42408 (2002).

    CAS  PubMed  Article  Google Scholar 

  27. Murali-Krishna, K. et al. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8, 177–187 (1998).

    CAS  PubMed  Article  Google Scholar 

  28. Shlomchik, W.D. Graft-versus-host disease. Nat. Rev. Immunol. 7, 340–352 (2007).

    CAS  PubMed  Article  Google Scholar 

  29. Welniak, L.A., Blazar, B.R. & Murphy, W.J. Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu. Rev. Immunol. 25, 139–170 (2007).

    CAS  PubMed  Article  Google Scholar 

  30. Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871–882 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Nie, Z. et al. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151, 68–79 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Peschon, J.J. et al. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J. Exp. Med. 180, 1955–1960 (1994).

    CAS  PubMed  Article  Google Scholar 

  33. Kerdiles, Y.M. et al. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat. Immunol. 10, 176–184 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Ouyang, W., Beckett, O., Flavell, R.A. & Li, M.O. An essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance. Immunity 30, 358–371 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Kaech, S.M. et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat. Immunol. 4, 1191–1198 (2003).

    CAS  PubMed  Article  Google Scholar 

  36. Tzachanis, D. et al. Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nat. Immunol. 2, 1174–1182 (2001).

    CAS  PubMed  Article  Google Scholar 

  37. Buckley, A.F., Kuo, C.T. & Leiden, J.M. Transcription factor LKLF is sufficient to program T cell quiescence via a c-Myc-dependent pathway. Nat. Immunol. 2, 698–704 (2001).

    CAS  PubMed  Article  Google Scholar 

  38. Potvin, E. et al. Cooperative action of multiple cis-acting elements is required for N-myc expression in branchial arches: specific contribution of GATA3. Mol. Cell. Biol. 30, 5348–5363 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Ouyang, W. et al. Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity 9, 745–755 (1998).

    CAS  PubMed  Article  Google Scholar 

  40. Yu, Q. et al. T cell factor 1 initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-γ. Nat. Immunol. 10, 992–999 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Amsen, D. et al. Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 117, 515–526 (2004).

    CAS  Article  PubMed  Google Scholar 

  42. Okamoto, M. et al. Essential role of Notch signaling in effector memory CD8+ T cell-mediated airway hyperresponsiveness and inflammation. J. Exp. Med. 205, 1087–1097 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Gattinoni, L. et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat. Med. 15, 808–813 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Morrot, A., Hafalla, J.C., Cockburn, I.A., Carvalho, L.H. & Zavala, F. IL-4 receptor expression on CD8+ T cells is required for the development of protective memory responses against liver stages of malaria parasites. J. Exp. Med. 202, 551–560 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Ku, C.J., Hosoya, T., Maillard, I. & Engel, J.D. GATA-3 regulates hematopoietic stem cell maintenance and cell-cycle entry. Blood 119, 2242–2251 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Liang, H.E. et al. Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat. Immunol. 13, 58–66 (2012).

    CAS  Article  Google Scholar 

  47. Lee, C.C., Huang, H.Y. & Chiang, B.L. Lentiviral-mediated GATA-3 RNAi decreases allergic airway inflammation and hyperresponsiveness. Mol. Ther. 16, 60–65 (2008).

    CAS  PubMed  Article  Google Scholar 

  48. Sel, S. et al. Effective prevention and therapy of experimental allergic asthma using a GATA-3-specific DNAzyme. J. Allergy Clin. Immunol. 121, 910–916 e915 (2008).

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

We thank M. Busslinger and A. Souabni (Research Institute of Molecular Pathology) for Gata3fl/fl mice; N. Fisher and J. Kalnitsky for cell sorting; and M. Su for discussions. Supported by the US National Institutes of Health (R01AI097392), National Multiple Sclerosis Society (RG4654) and the University Cancer Research Fund (Y.Y.W.).

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Y.W. designed and did cellular, molecular and biochemical experiments; Y.W., I.M. and J.K.W. did LCMV-infection experiments and contributed to the writing of the manuscript; A.-D.G. contributed to the graft-versus-host response experiments; T.A.C. and L.S. provided critical genetic models and intellectual inputs; and Y.Y.W. designed experiments, wrote the manuscript and provided overall direction.

Corresponding author

Correspondence to Yisong Y Wan.

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The authors declare no competing financial interests.

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Wang, Y., Misumi, I., Gu, AD. et al. GATA-3 controls the maintenance and proliferation of T cells downstream of TCR and cytokine signaling. Nat Immunol 14, 714–722 (2013). https://doi.org/10.1038/ni.2623

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