title: IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection.
abstract: Suppression of T-cell responses by host-derived regulatory factors is a key event leading to viral persistence. Antibody blockade of either IL-10 or programmed death-ligand 1 (PD-L1) during viral persistence enhances T-cell function and reduces viral titers. Because blockade of these immunoregulatory networks represents a powerful approach to establish immune control during persistent infection, it is important to determine whether these immunoinhibitory factors act independently or jointly and if combined blockade of these factors further enhances T-cell immunity and viral clearance. Herein, we demonstrate that the IL-10 and PD-L1 immunosuppressive pathways are mechanistically distinct. As a result, simultaneous blockade of IL-10 and PD-L1 was significantly more effective in restoring antiviral T-cell responses than blockade of either alone, and led to substantially enhanced control of an established persistent viral infection. Thus, combinatorial blockade of multiple immune-regulatory molecules may ultimately restore the T-cell responses required to tip the balance from viral persistence to immune-mediated control or elimination of persistent infection.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, and the UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles CA 90095, USA. dbrooks@em.ucla.edu
authors.forename: David G
authors.initials: DG
authors.lastname: Brooks
authors.forename: Sang-Jun
authors.initials: SJ
authors.lastname: Ha
authors.forename: Heidi
authors.initials: H
authors.lastname: Elsaesser
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Michael B A
authors.initials: MB
authors.lastname: Oldstone
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D015703:Antigens, CD / Q000187:drug effects / Q000502:physiology*; D060890:B7-H1 Antigen; D004359:Drug Therapy, Combination; D007109:Immunity / Q000187:drug effects; D007167:Immunotherapy / Q000379:methods; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014777:Virus Diseases / Q000276:immunology* / Q000628:therapy*
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016753:Interleukin-10