TGF-β regulates the stem-like state of PD-1+ TCF-1+ virus-specific CD8 T cells during chronic infection

J Exp Med. 2022 Oct 3;219(10):e20211574. doi: 10.1084/jem.20211574. Epub 2022 Aug 18.


Recent studies have defined a novel population of PD-1+ TCF-1+ stem-like CD8 T cells in chronic infections and cancer. These quiescent cells reside in lymphoid tissues, are critical for maintaining the CD8 T cell response under conditions of persistent antigen, and provide the proliferative burst after PD-1 blockade. Here we examined the role of TGF-β in regulating the differentiation of virus-specific CD8 T cells during chronic LCMV infection of mice. We found that TGF-β signaling was not essential for the generation of the stem-like CD8 T cells but was critical for maintaining the stem-like state and quiescence of these cells. TGF-β regulated the unique transcriptional program of the stem-like subset, including upregulation of inhibitory receptors specifically expressed on these cells. TGF-β also promoted the terminal differentiation of exhausted CD8 T cells by suppressing the effector-associated program. Together, the absence of TGF-β signaling resulted in significantly increased accumulation of effector-like CD8 T cells. These findings have implications for immunotherapies in general and especially for T cell therapy against chronic infections and cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes
  • Lymphocytic Choriomeningitis*
  • Lymphocytic choriomeningitis virus / physiology
  • Mice
  • Neoplasms*
  • Persistent Infection
  • Programmed Cell Death 1 Receptor
  • Transforming Growth Factor beta


  • Programmed Cell Death 1 Receptor
  • Transforming Growth Factor beta