Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance

Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):E7536-E7544. doi: 10.1073/pnas.1706356114. Epub 2017 Aug 21.


Peripheral T cell tolerance is promoted by the regulatory cytokine TGF-β and Foxp3-expressing Treg cells. However, whether TGF-β and Treg cells are part of the same regulatory module, or exist largely as distinct pathways to repress self-reactive T cells remains incompletely understood. Using a transgenic model of autoimmune diabetes, here we show that ablation of TGF-β receptor II (TβRII) in T cells, but not Foxp3 deficiency, resulted in early-onset diabetes with complete penetrance. The rampant autoimmune disease was associated with enhanced T cell priming and elevated T cell expression of the inflammatory cytokine GM-CSF, concomitant with pancreatic infiltration of inflammatory monocytes that triggered immunopathology. Ablation of the GM-CSF receptor alleviated the monocyte response and inhibited disease development. These findings reveal that TGF-β promotes T cell tolerance primarily via Foxp3-independent mechanisms and prevents autoimmunity in this model by repressing the cross talk between adaptive and innate immune systems.

Keywords: T cell; TGF-β; autoimmunity; tolerance.

Publication types

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

MeSH terms

  • Adaptive Immunity / immunology
  • Animals
  • Autoimmunity / immunology
  • Cytokines / metabolism
  • Forkhead Transcription Factors / metabolism*
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Immunity, Innate / immunology
  • Inflammation / metabolism
  • Mice
  • Peripheral Tolerance / immunology*
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • Transforming Growth Factor beta / metabolism*


  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Transforming Growth Factor beta
  • Granulocyte-Macrophage Colony-Stimulating Factor