title: Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection.
abstract: Regulatory T (T reg) cells are critical for preventing autoimmunity mediated by self-reactive T cells, but their role in modulating immune responses during chronic viral infection is not well defined. To address this question and to investigate a role for T reg cells in exhaustion of virus-specific CD8 T cells, we depleted T reg cells in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). T reg cell ablation resulted in 10-100-fold expansion of functional LCMV-specific CD8 T cells. Rescue of exhausted CD8 T cells was dependent on cognate antigen, B7 costimulation, and conventional CD4 T cells. Despite the striking recovery of LCMV-specific CD8 T cell responses, T reg cell depletion failed to diminish viral load. Interestingly, T reg cell ablation triggered up-regulation of the molecule programmed cell death ligand-1 (PD-L1), which upon binding PD-1 on T cells delivers inhibitory signals. Increased PD-L1 expression was observed especially on LCMV-infected cells, and combining T reg cell depletion with PD-L1 blockade resulted in a significant reduction in viral titers, which was more pronounced than that upon PD-L1 blockade alone. These results suggest that T reg cells effectively maintain CD8 T cell exhaustion, but blockade of the PD-1 inhibitory pathway is critical for elimination of infected cells.
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Pablo
authors.initials: P
authors.lastname: Penaloza-MacMaster
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Alice O
authors.initials: AO
authors.lastname: Kamphorst
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wieland
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Koichi
authors.initials: K
authors.lastname: Araki
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Smita S
authors.initials: SS
authors.lastname: Iyer
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Erin E
authors.initials: EE
authors.lastname: West
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Leigh
authors.initials: L
authors.lastname: O'Mara
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322 Xiangya School of Medicine, Central South University, Changsha, Hunan Province, 410013, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Yang
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Bogumila T
authors.initials: BT
authors.lastname: Konieczny
authors.affiliation: Department of Microbiology and Immunology, and Department of Medical Oncology and Dana Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115.
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.affiliation: Department of Microbiology and Immunology, and Department of Medical Oncology and Dana Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Howard Hughes Medical Institute, Immunology Program, Sloan-Kettering Institute for Cancer Research, and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Howard Hughes Medical Institute, Immunology Program, Sloan-Kettering Institute for Cancer Research, and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Howard Hughes Medical Institute, Immunology Program, Sloan-Kettering Institute for Cancer Research, and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, NY 10065 rahmed@emory.edu rudenska@mskcc.org.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322 rahmed@emory.edu rudenska@mskcc.org.
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002908:Chronic Disease; D003713:Dendritic Cells / Q000276:immunology; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000821:virology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D015854:Up-Regulation
chemical_list: C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor
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