title: CD8+ T cell exhaustion during persistent viral infection is regulated independently of the virus-specific T cell receptor.
abstract: During chronic viral infections, responses by virus-specific CD8(+) T cells become marginalized by the acquisition of functional defects and reduced cell numbers in a process defined as T cell exhaustion. Similarly, T cell tolerance to self-antigen is also characterized by impaired effector function and eventual deletion of self-reactive T cells. Induction of both tolerance and exhaustion involve many shared inhibitory mechanisms, thus similar therapeutic approaches have proven effective in these distinct environments. We previously demonstrated that tolerant self-reactive CD8(+) T cells expressing dual-T cell receptors (i.e., dual-TCR) could be rescued by immunization through a second TCR specific for a foreign antigen. These data revealed that T cell tolerance was regulated at the level of the self-reactive TCR. Here, dual-TCR CD8(+) T cells were used to examine if exhaustion during persistent viral infection could be rescued by an analogous strategy of immunization through a second TCR not involved in recognition of virus. In direct contrast to the rescue achievable in tolerant CD8(+) T cells, exhausted T cells were equally impaired through both TCR. These findings suggest that exhaustion is maintained by defects downstream of the virus-specific TCR, and establish that exhaustion and tolerance are distinctly regulated states of T cell dysfunction.
authors: Saint Louis University School of Medicine, Department of Molecular Microbiologyand Immunology, St Louis, Missouri 63104, USA.
authors: Stephanie R
authors: SR
authors: Jackson
authors: Melissa M
authors: MM
authors: Berrien-Elliott
authors: Jennifer M
authors: JM
authors: Meyer
authors: E John
authors: EJ
authors: Wherry
authors: Ryan M
authors: RM
authors: Teague
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation / Q000821:virology; D002908:Chronic Disease; D006801:Humans; D007114:Immunization; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000503:physiopathology* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*
chemical_list: D000956:Antigens, Viral; D011948:Receptors, Antigen, T-Cell