Tolerance and exhaustion: defining mechanisms of T cell dysfunction

Trends Immunol. 2014 Feb;35(2):51-60. doi: 10.1016/ Epub 2013 Nov 6.


CD8 T cell activation and differentiation are tightly controlled, and dependent on the context in which naïve T cells encounter antigen, can either result in functional memory or T cell dysfunction, including exhaustion, tolerance, anergy, or senescence. With the identification of phenotypic and functional traits shared in different settings of T cell dysfunction, distinctions between such dysfunctional states have become blurred. Here, we discuss distinct states of CD8 T cell dysfunction, with an emphasis on: (i) T cell tolerance to self-antigens (self-tolerance); (ii) T cell exhaustion during chronic infections; and (iii) tumor-induced T cell dysfunction. We highlight recent findings on cellular and molecular characteristics defining these states, cell-intrinsic regulatory mechanisms that induce and maintain them, and strategies that can lead to their reversal.

Keywords: CD8 T cells; T cell differentiation; T cell dysfunction; chronic infection; exhaustion; self-tolerance; tumors.

Publication types

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

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Differentiation / immunology
  • Clonal Anergy
  • Epigenesis, Genetic
  • Humans
  • Immune Tolerance* / genetics
  • Immunologic Memory
  • Infections / immunology
  • Lymphocyte Activation
  • Mice
  • Neoplasms / immunology
  • Self Tolerance