title: Overcoming CD4 Th1 Cell Fate Restrictions to Sustain Antiviral CD8 T Cells and Control Persistent Virus Infection.
abstract: Viral persistence specifically inhibits CD4 Th1 responses and promotes Tfh immunity, but the mechanisms that suppress Th1 cells and the disease consequences of their loss are unclear. Here, we demonstrate that the loss of CD4 Th1 cells specifically leads to progressive CD8 T cell decline and dysfunction during viral persistence. Therapeutically reconstituting CD4 Th1 cells restored CD4 T cell polyfunctionality, enhanced antiviral CD8 T cell numbers and function, and enabled viral control. Mechanistically, combined interaction of PD-L1 and IL-10 by suppressive dendritic cell subsets inhibited new CD4 Th1 cells in both acute and persistent virus infection, demonstrating an unrecognized suppressive function for PD-L1 in virus infection. Thus, the loss of CD4 Th1 cells is a key event leading to progressive CD8 T cell demise during viral persistence with important implications for restoring antiviral CD8 T cell immunity to control persistent viral infection.
authors.affiliation: Princess Margaret Cancer Center, Immune Therapy Program, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Snell
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Osokine
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Yamada
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Justin Rafael
authors.initials: JR
authors.lastname: De la Fuente
authors.affiliation: Princess Margaret Cancer Center, Immune Therapy Program, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Elsaesser
authors.affiliation: Princess Margaret Cancer Center, Immune Therapy Program, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: dbrooks@uhnresearch.ca.
authors.forename: David G
authors.initials: DG
authors.lastname: Brooks
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C556062:IL10 protein, mouse; D016753:Interleukin-10