Article | Published:

Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses

Nature Immunology volume 16, pages 178187 (2015) | Download Citation

Abstract

The interplay between effector T cells and regulatory T cells (Treg cells) is crucial for adaptive immunity, but how Treg cells control diverse effector responses is elusive. We found that the phosphatase PTEN links Treg cell stability to repression of type 1 helper T cell (TH1 cell) and follicular helper T cell (TFH cell) responses. Depletion of PTEN in Treg cells resulted in excessive TFH cell and germinal center responses and spontaneous inflammatory disease. These defects were considerably blocked by deletion of interferon-γ, indicating coordinated control of TH1 and TFH responses. Mechanistically, PTEN maintained Treg cell stability and metabolic balance between glycolysis and mitochondrial fitness. Moreover, PTEN deficiency upregulates activity of the metabolic checkpoint kinase complex mTORC2 and the serine-threonine kinase Akt, and loss of this activity restores functioning of PTEN-deficient Treg cells. Our studies establish a PTEN-mTORC2 axis that maintains Treg cell stability and coordinates Treg cell–mediated control of effector responses.

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References

  1. 1.

    , & Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531–564 (2012).

  2. 2.

    , , , & The plasticity and stability of regulatory T cells. Nat. Rev. Immunol. 13, 461–467 (2013).

  3. 3.

    et al. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 10, 595–602 (2009).

  4. 4.

    et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses. Nature 458, 351–356 (2009).

  5. 5.

    et al. CD4+ regulatory t cells control TH17 responses in a Stat3-dependent manner. Science 326, 986–991 (2009).

  6. 6.

    et al. Stability of the regulatory T cell lineage in vivo. Science 329, 1667–1671 (2010).

  7. 7.

    et al. Novel Foxo1-dependent transcriptional programs control Treg cell function. Nature 491, 554–559 (2012).

  8. 8.

    et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 10, 1000–1007 (2009).

  9. 9.

    et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 323, 1488–1492 (2009).

  10. 10.

    et al. Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity 39, 949–962 (2013).

  11. 11.

    et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat. Med. 20, 62–68 (2014).

  12. 12.

    et al. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc. Natl. Acad. Sci. USA 106, 1903–1908 (2009).

  13. 13.

    et al. Plasticity of Foxp3+ T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 36, 262–275 (2012).

  14. 14.

    et al. CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J. Exp. Med. 211, 121–136 (2014).

  15. 15.

    Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621–663 (2011).

  16. 16.

    et al. Follicular helper T cells are required for systemic autoimmunity. J. Exp. Med. 206, 561–576 (2009).

  17. 17.

    et al. Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. Nature 507, 513–518 (2014).

  18. 18.

    et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 17, 983–988 (2011).

  19. 19.

    et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med. 17, 975–982 (2011).

  20. 20.

    Regulation and function of mTOR signalling in T cell fate decisions. Nat. Rev. Immunol. 12, 325–338 (2012).

  21. 21.

    , , & Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30, 39–68 (2012).

  22. 22.

    et al. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 32, 743–753 (2010).

  23. 23.

    et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12, 295–303 (2011).

  24. 24.

    et al. T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. Immunity 39, 1043–1056 (2013).

  25. 25.

    et al. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature 499, 485–490 (2013).

  26. 26.

    , , , & The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat. Immunol. 12, 888–897 (2011).

  27. 27.

    et al. T cell–specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 14, 523–534 (2001).

  28. 28.

    et al. Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice. J. Clin. Invest. 120, 2497–2507 (2010).

  29. 29.

    et al. Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner. Cell 144, 187–199 (2011).

  30. 30.

    et al. Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J. Immunol. 172, 5287–5296 (2004).

  31. 31.

    et al. Scaffold protein Disc large homolog 1 is required for T-cell receptor-induced activation of regulatory T-cell function. Proc. Natl. Acad. Sci. USA 109, 1625–1630 (2012).

  32. 32.

    et al. Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 501, 252–256 (2013).

  33. 33.

    et al. PTEN inhibits IL-2 receptor-mediated expansion of CD4+ CD25+ Tregs. J. Clin. Invest. 116, 2521–2531 (2006).

  34. 34.

    et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008).

  35. 35.

    et al. Interferon-γ excess leads to pathogenic accumulation of follicular helper T cells and germinal centers. Immunity 37, 880–892 (2012).

  36. 36.

    et al. Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity 35, 919–931 (2011).

  37. 37.

    et al. Transcription factor STAT3 and type I interferons are corepressive insulators for differentiation of follicular helper and T helper 1 cells. Immunity 40, 367–377 (2014).

  38. 38.

    et al. Epigenetic modifications induced by Blimp-1 Regulate CD8+ T cell memory progression during acute virus infection. Immunity 39, 661–675 (2013).

  39. 39.

    et al. The transcription factor Foxp1 is a critical negative regulator of the differentiation of follicular helper T cells. Nat. Immunol. 15, 667–675 (2014).

  40. 40.

    et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

  41. 41.

    et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186, 3299–3303 (2011).

  42. 42.

    et al. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367–1376 (2011).

  43. 43.

    et al. Phosphatase PTEN–mediated control of the kinase PI(3)K in Treg cells maintains homeostasis and lineage stability. Nat. Immunol. (5 January 2015).

  44. 44.

    , , , & Homeostasis and anergy of CD4+CD25+ suppressor T cells in vivo. Nat. Immunol. 3, 33–41 (2002).

  45. 45.

    , , , & FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability. Nat. Commun. 5, 3495 (2014).

  46. 46.

    et al. Pten loss in CD4 T cells enhances their helper function but does not lead to autoimmunity or lymphoma. J. Immunol. 188, 5935–5943 (2012).

  47. 47.

    et al. MicroRNAs of the miR-1792 family are critical regulators of TFH differentiation. Nat. Immunol. 14, 849–857 (2013).

  48. 48.

    et al. Systemic elevation of PTEN induces a tumor-suppressive metabolic state. Cell 149, 49–62 (2012).

  49. 49.

    , & Cutting edge: discrete functions of mTOR signaling in invariant NKT cell development and NKT17 fate decision. J. Immunol. 193, 4297–4301 (2014).

  50. 50.

    et al. The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR. Nat. Immunol. 10, 769–777 (2009).

  51. 51.

    , , , & The S1P(1)-mTOR axis directs the reciprocal differentiation of TH1 and Treg cells. Nat. Immunol. 11, 1047–1056 (2010).

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Acknowledgements

The authors thank J. Wei, D. Bastardo Blanco and S. Brown for help with immunological assays; C. Cloer and B. Rhode for animal colony management; A. Rudensky for Foxp3YFP-Cre mice and the St. Jude Immunology FACS core facility for cell sorting. Supported by US National Institutes of Health (AI105887, AI101407, CA176624 and NS064599 to H.C.), the American Cancer Society (to H.C.) and the Crohn's and Colitis Foundation of America (to H.C.), and the Arthritis Foundation (to K.Y.).

Author information

Author notes

    • Sharad Shrestha
    •  & Kai Yang

    These authors contributed equally to this work.

Affiliations

  1. Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Sharad Shrestha
    • , Kai Yang
    • , Cliff Guy
    •  & Hongbo Chi
  2. Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, Tennessee, USA.

    • Sharad Shrestha
    •  & Hongbo Chi
  3. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Peter Vogel
  4. Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Geoffrey Neale

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Contributions

S.S. and K.Y. designed and performed cellular, molecular and biochemical experiments and contributed to writing the manuscript; C.G. did imaging assays; P.V. did histopathology analysis; G.N. did bioinformatic analyses; and H.C. designed experiments, wrote the manuscript and provided overall direction.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Hongbo Chi.

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DOI

https://doi.org/10.1038/ni.3076

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