Dynamic adoption of anergy by antigen-exhausted CD4+ T cells

Cell Rep. 2021 Feb 9;34(6):108748. doi: 10.1016/j.celrep.2021.108748.


Exhausted immune responses to chronic diseases represent a major challenge to global health. We study CD4+ T cells in a mouse model with regulatable antigen presentation. When the cells are driven through the effector phase and are then exposed to different levels of persistent antigen, they lose their T helper 1 (Th1) functions, upregulate exhaustion markers, resemble naturally anergic cells, and modulate their MAPK, mTORC1, and Ca2+/calcineurin signaling pathways with increasing dose and time. They also become unable to help B cells and, at the highest dose, undergo apoptosis. Transcriptomic analyses show the dynamic adjustment of gene expression and the accumulation of T cell receptor (TCR) signals over a period of weeks. Upon antigen removal, the cells recover their functionality while losing exhaustion and anergy markers. Our data suggest an adjustable response of CD4+ T cells to different levels of persisting antigen and contribute to a better understanding of chronic disease.

Keywords: CD4(+) T cells; T cell receptor; anergy; exhaustion; gene expression; microarray; tolerance; transcriptomics; tuning.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens / genetics
  • Antigens / immunology*
  • B-Lymphocytes / immunology
  • Calcium Signaling / genetics
  • Calcium Signaling / immunology*
  • Clonal Anergy*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation / immunology*
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / immunology*
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / immunology
  • Mice
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Th1 Cells / immunology*


  • Antigens
  • Receptors, Antigen, T-Cell
  • Mechanistic Target of Rapamycin Complex 1