title: Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection.
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.
authors.affiliation: Immunology Program and Wistar Vaccine Center, Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Blackburn
authors.forename: Haina
authors.initials: H
authors.lastname: Shin
authors.forename: W Nicholas
authors.initials: WN
authors.lastname: Haining
authors.forename: Tao
authors.initials: T
authors.lastname: Zou
authors.forename: Creg J
authors.initials: CJ
authors.lastname: Workman
authors.forename: Antonio
authors.initials: A
authors.lastname: Polley
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D000954:Antigens, Surface / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002908:Chronic Disease; D004195:Disease Models, Animal; D015536:Down-Regulation; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000378:metabolism; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic / Q000378:metabolism*; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D000093322:Lymphocyte Activation Gene 3 Protein