title: Programmed death 1-mediated T cell exhaustion during visceral leishmaniasis impairs phagocyte function.
abstract: Control of Leishmania infantum infection is dependent upon Th1 CD4(+) T cells to promote macrophage intracellular clearance of parasites. Deficient CD4(+) T cell effector responses during clinical visceral leishmaniasis (VL) are associated with elevated production of IL-10. In the primary domestic reservoir of VL, dogs, we define occurrence of both CD4(+) and CD8(+) T cell exhaustion as a significant stepwise loss of Ag-specific proliferation and IFN-γ production, corresponding to increasing VL symptoms. Exhaustion was associated with a 4-fold increase in the population of T cells with surface expression of programmed death 1 (PD-1) between control and symptomatic populations. Importantly, exhausted populations of CD8(+) T cells and to a lesser extent CD4(+) T cells were present prior to onset of clinical VL. VL-exhausted T cells did not undergo significant apoptosis ex vivo after Ag stimulation. Ab block of PD-1 ligand, B7.H1, promoted return of CD4(+) and CD8(+) T cell function and dramatically increased reactive oxygen species production in cocultured monocyte-derived phagocytes. As a result, these phagocytes had decreased parasite load. To our knowledge, we demonstrate for the first time that pan-T cell, PD-1-mediated, exhaustion during VL influenced macrophage-reactive oxygen intermediate production. Blockade of the PD-1 pathway improved the ability of phagocytes isolated from dogs presenting with clinical VL to clear intracellular parasites. T cell exhaustion during symptomatic canine leishmaniasis has implications for the response to vaccination and therapeutic strategies for control of Leishmania infantum in this important reservoir species.
authors.affiliation: Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Esch
authors.forename: Rachel
authors.initials: R
authors.lastname: Juelsgaard
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Martinez
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Jones
authors.forename: Christine A
authors.initials: CA
authors.lastname: Petersen
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000187:drug effects; D018920:Coculture Techniques; D004285:Dogs; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018314:Leishmania infantum / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000276:immunology / Q000662:veterinary*; D018384:Oxidative Stress / Q000187:drug effects; D059208:Parasite Load; D010586:Phagocytes / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D019138:Antibodies, Blocking; D060890:B7-H1 Antigen; D061026:Programmed Cell Death 1 Receptor; D017382:Reactive Oxygen Species; D016753:Interleukin-10; D007371:Interferon-gamma