Transforming growth factor-β-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection

Immunity. 2021 Aug 10;54(8):1698-1714.e5. doi: 10.1016/j.immuni.2021.06.007. Epub 2021 Jul 6.


Antigen-specific CD8+ T cells in chronic viral infections and tumors functionally deteriorate, a process known as exhaustion. Exhausted T cells are sustained by precursors of exhausted (Tpex) cells that self-renew while continuously generating exhausted effector (Tex) cells. However, it remains unknown how Tpex cells maintain their functionality. Here, we demonstrate that Tpex cells sustained mitochondrial fitness, including high spare respiratory capacity, while Tex cells deteriorated metabolically over time. Tpex cells showed early suppression of mTOR kinase signaling but retained the ability to activate this pathway in response to antigen receptor signals. Early transient mTOR inhibition improved long-term T cell responses and checkpoint inhibition. Transforming growth factor-β repressed mTOR signaling in exhausted T cells and was a critical determinant of Tpex cell metabolism and function. Overall, we demonstrate that the preservation of cellular metabolism allows Tpex cells to retain long-term functionality to sustain T cell responses during chronic infection.

Keywords: OXPHOS; T cell exhaustion; T cell function; TCF1; checkpoint inhibition; mitochondria; precursors of exhausted T cells; progenitor T cells; rapamycin; stem-like T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • Energy Metabolism / physiology*
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic choriomeningitis virus / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / metabolism
  • Signal Transduction / immunology
  • TOR Serine-Threonine Kinases / metabolism*
  • Transforming Growth Factor beta1 / metabolism*


  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta1
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases