Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection

Nat Immunol. 2009 Jan;10(1):29-37. doi: 10.1038/ni.1679. Epub 2008 Nov 30.

Abstract

T cell exhaustion often occurs during chronic infection and prevents optimal viral control. The molecular pathways involved in T cell exhaustion remain poorly understood. Here we show that exhausted CD8+ T cells are subject to complex layers of negative regulation resulting from the coexpression of multiple inhibitory receptors. Exhausted CD8+ T cells expressed up to seven inhibitory receptors. Coexpression of multiple distinct inhibitory receptors was associated with greater T cell exhaustion and more severe infection. Regulation of T cell exhaustion by various inhibitory pathways was nonredundant, as blockade of the T cell inhibitory receptors PD-1 and LAG-3 simultaneously and synergistically improved T cell responses and diminished viral load in vivo. Thus, CD8+ T cell responses during chronic viral infections are regulated by complex patterns of coexpressed inhibitory receptors.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • Antigens, Surface / metabolism*
  • Apoptosis Regulatory Proteins / metabolism*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology
  • Chronic Disease
  • Disease Models, Animal
  • Down-Regulation
  • Immunologic Memory
  • Lymphocyte Activation*
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic Choriomeningitis / metabolism
  • Lymphocytic choriomeningitis virus
  • Mice
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic / metabolism*

Substances

  • Antigens, CD
  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • CD223 antigen
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic