High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival

J Exp Med. 2016 Aug 22;213(9):1819-34. doi: 10.1084/jem.20150598. Epub 2016 Jul 25.


Chronic infections induce T cells showing impaired cytokine secretion and up-regulated expression of inhibitory receptors such as PD-1. What determines the acquisition of this chronic phenotype and how it impacts T cell function remain vaguely understood. Using newly generated recombinant antigen variant-expressing chronic lymphocytic choriomeningitis virus (LCMV) strains, we uncovered that T cell differentiation and acquisition of a chronic or exhausted phenotype depend critically on the frequency of T cell receptor (TCR) engagement and less significantly on the strength of TCR stimulation. In fact, we noted that low-level antigen exposure promotes the formation of T cells with an acute phenotype in chronic infections. Unexpectedly, we found that T cell populations with an acute or chronic phenotype are maintained equally well in chronic infections and undergo comparable primary and secondary expansion. Thus, our observations contrast with the view that T cells with a typical chronic infection phenotype are severely functionally impaired and rapidly transition into a terminal stage of differentiation. Instead, our data unravel that T cells primarily undergo a form of phenotypic and functional differentiation in the early phase of a chronic LCMV infection without inheriting a net survival or expansion deficit, and we demonstrate that the acquired chronic phenotype transitions into the memory T cell compartment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / analysis
  • Antigens, Viral / blood*
  • Cell Differentiation
  • Cell Survival
  • Chronic Disease
  • Interleukin-7 Receptor alpha Subunit / analysis
  • Lymphocyte Activation
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic choriomeningitis virus / immunology
  • Mice
  • Mice, Inbred C57BL
  • Phenotype
  • Programmed Cell Death 1 Receptor / analysis
  • Receptors, Antigen, T-Cell / physiology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / physiology*


  • Antigens, CD
  • Antigens, Viral
  • CD223 antigen
  • Interleukin-7 Receptor alpha Subunit
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell