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

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


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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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.).

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Author notes

    • Sharad Shrestha
    •  & Kai Yang

    These authors contributed equally to this work.


  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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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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