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Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability

Nature Immunology volume 16, pages 188196 (2015) | Download Citation

Abstract

Foxp3+ regulatory T cells (Treg cells) are required for immunological homeostasis. One notable distinction between conventional T cells (Tconv cells) and Treg cells is differences in the activity of phosphatidylinositol-3-OH kinase (PI(3)K); only Tconv cells downregulate PTEN, the main negative regulator of PI(3)K, upon activation. Here we found that control of PI(3)K in Treg cells was essential for lineage homeostasis and stability. Mice lacking Pten in Treg cells developed an autoimmune-lymphoproliferative disease characterized by excessive T helper type 1 (TH1) responses and B cell activation. Diminished control of PI(3)K activity in Treg cells led to reduced expression of the interleukin-2 (IL-2) receptor α subunit CD25, accumulation of Foxp3+CD25 cells and, ultimately, loss of expression of the transcription factor Foxp3 in these cells. Collectively, our data demonstrate that control of PI(3)K signaling by PTEN in Treg cells is critical for maintaining their homeostasis, function and stability.

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Acknowledgements

We thank A. Rudensky (Memorial Sloan Kettering Cancer Center) for Foxp3-YFP-Cre mice and Foxp3eGFP–Cre–ERT2Rosa26-YFP mice. Supported by the US National Institutes of Health (R56AI083304 and 01HL018646 to L.A.T.; R21AI105607 to L.A.T. and J.A.B.; T32AI007529 to C.M.B.; and P01AI56299 to P.T.S., A.H.S. and L.A.T.), the Cancer Research Institute (A.H.) and (1S10RR023440).

Author information

Affiliations

  1. Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.

    • Alexandria Huynh
    • , Christopher M Borges
    •  & Laurence A Turka
  2. Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Alexandria Huynh
    • , Bhavana Priyadharshini
    • , Christopher M Borges
    •  & Laurence A Turka
  3. Diabetes Center and the Department of Medicine, University of California–San Francisco, San Francisco, California, USA.

    • Michel DuPage
    • , Jason Quiros
    •  & Jeffrey A Bluestone
  4. Division of Immunology, Department of Microbiology, Harvard Medical School, Boston, Massachusetts, USA.

    • Peter T Sage
    •  & Arlene H Sharpe
  5. Division of Nephrology, Department of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand.

    • Natavudh Townamchai
  6. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.

    • Valerie A Gerriets
    •  & Jeffrey C Rathmell

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Contributions

A.H., M.D., B.P., P.T.S., J.Q., N.T. and V.A.G. designed and performed experiments; C.M.B., J.C.R. and A.H.S. designed experiments; A.H., M.D., J.A.B. and L.A.T. designed the study; and A.H. and L.A.T., with assistance from M.D. and J.A.B., wrote the manuscript.

Competing interests

L.A.T. owns equity in and has a family member employed by Novartis.

Corresponding author

Correspondence to Laurence A Turka.

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DOI

https://doi.org/10.1038/ni.3077

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