title: Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection.
abstract: Inhibitory receptors play a crucial role in regulating CD8 T-cell function during chronic viral infection. T-cell Ig- and mucin-domain-containing molecule-3 (Tim-3) is well known to negatively regulate T-cell responses, but its role in CD8 T-cell exhaustion during chronic infection in vivo remains unclear. In this study, we document coregulation of CD8 T cell exhaustion by Tim-3 and PD-1 during chronic lymphocytic choriomeningitis virus infection. Whereas Tim-3 was only transiently expressed by CD8 T cells after acute infection, virus-specific CD8 T cells retained high Tim-3 expression throughout chronic infection. The majority (approximately 65% to 80%) of lymphocytic choriomeningitis virus-specific CD8 T cells in lymphoid and nonlymphoid organs coexpressed Tim-3 and PD-1. This coexpression of Tim-3 and PD-1 was associated with more severe CD8 T-cell exhaustion in terms of proliferation and secretion of effector cytokines such as IFN-gamma, TNF-alpha, and IL-2. Interestingly, CD8 T cells expressing both inhibitory receptors also produced the suppressive cytokine IL-10. Most importantly, combined blockade of Tim-3 and PD-1 pathways in vivo synergistically improved CD8 T cell responses and viral control in chronically infected mice. Taken together, our study defines a parameter for determining the severity of CD8 T cell dysfunction and for identifying virus-specific CD8 T cells that produce IL-10, and shows that targeting both PD-1 and Tim-3 is an effective immune strategy for treating chronic viral infections.
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Emory Vaccine Center, Atlanta, GA 30322, USA.
authors.forename: Hyun-Tak
authors.initials: HT
authors.lastname: Jin
authors.forename: Ana C
authors.initials: AC
authors.lastname: Anderson
authors.forename: Wendy G
authors.initials: WG
authors.lastname: Tan
authors.forename: Erin E
authors.initials: EE
authors.lastname: West
authors.forename: Sang-Jun
authors.initials: SJ
authors.lastname: Ha
authors.forename: Koichi
authors.initials: K
authors.lastname: Araki
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology; D000954:Antigens, Surface / Q000276:immunology* / Q000378:metabolism; D000956:Antigens, Viral / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002908:Chronic Disease; D005260:Female; D005434:Flow Cytometry; D000072597:Hepatitis A Virus Cellular Receptor 2; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor; D011991:Receptors, Virus / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D000954:Antigens, Surface; D000956:Antigens, Viral; D051017:Apoptosis Regulatory Proteins; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D007376:Interleukin-2; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011991:Receptors, Virus; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma