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

Nat Immunol. 2015 Feb;16(2):178-87. doi: 10.1038/ni.3076. Epub 2015 Jan 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Lymphocyte Activation
  • Mice
  • PTEN Phosphohydrolase / metabolism*
  • Repressor Proteins / metabolism
  • Signal Transduction
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Regulatory / enzymology*
  • T-Lymphocytes, Regulatory / immunology*
  • Th1 Cells / enzymology
  • Th1 Cells / immunology*

Substances

  • Forkhead Transcription Factors
  • Foxp1 protein, mouse
  • Repressor Proteins
  • PTEN Phosphohydrolase
  • PTEN protein, human