Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection

J Virol. 2012 Aug;86(15):8161-70. doi: 10.1128/JVI.00889-12. Epub 2012 May 23.

Abstract

T cell exhaustion and loss of memory potential occur during many chronic viral infections and cancer. We investigated when during chronic viral infection virus-specific CD8 T cells lose the potential to form memory. Virus-specific CD8 T cells from established chronic infection were unable to become memory CD8 T cells if removed from infection. However, at earlier stages of chronic infection, these virus-specific CD8 T cells retained the potential to partially or fully revert to a memory differentiation program after transfer to infection-free mice. Conversely, effector CD8 T cells primed during acute infection were not protected from exhaustion if transferred to a chronic infection. We also tested whether memory and exhausted CD8 T cells arose from different subpopulations of effector CD8 T cells and found that only the KLRG1(lo) memory precursor subset gave rise to exhausted CD8 T cells. Together, these studies demonstrate that CD8 T cell exhaustion is a progressive developmental process. Early during chronic infection, the fate of virus-specific CD8 T cells remains plastic, while later, exhausted CD8 T cells become fixed in their differentiation state. Moreover, exhausted CD8 T cells arise from the memory precursor and not the terminally differentiated subset of effector CD8 T cells. These studies have implications for our understanding of senescence versus exhaustion and for therapeutic interventions during chronic infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Differentiation / immunology*
  • Chronic Disease
  • Immunologic Memory*
  • Lectins, C-Type
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic Choriomeningitis / pathology
  • Lymphocytic choriomeningitis virus / immunology*
  • Mice
  • Precursor Cells, T-Lymphoid / immunology*
  • Precursor Cells, T-Lymphoid / pathology
  • Receptors, Immunologic / immunology

Substances

  • Klrg1 protein, mouse
  • Lectins, C-Type
  • Receptors, Immunologic