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Programmed death 1-mediated T cell exhaustion during visceral leishmaniasis impairs phagocyte function
Journal article   Peer reviewed

Programmed death 1-mediated T cell exhaustion during visceral leishmaniasis impairs phagocyte function

Kevin J Esch, Rachel Juelsgaard, Pedro A Martinez, Douglas E Jones and Christine A Petersen
The Journal of immunology (1950), Vol.191(11), pp.5542-5550
12/01/2013
DOI: 10.4049/jimmunol.1301810
PMCID: PMC3896087
PMID: 24154626

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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.
 Up-Regulation Reactive Oxygen Species - metabolism Coculture Techniques Humans Programmed Cell Death 1 Receptor - antagonists & inhibitors Antibodies, Blocking - pharmacology Leishmaniasis, Visceral - immunology Interferon-gamma - metabolism CD4-Positive T-Lymphocytes - immunology Leishmaniasis, Visceral - veterinary Clonal Anergy - drug effects Interleukin-10 - metabolism CD4-Positive T-Lymphocytes - microbiology CD8-Positive T-Lymphocytes - microbiology Phagocytes - drug effects Parasite Load Cells, Cultured Programmed Cell Death 1 Receptor - metabolism Phagocytes - immunology B7-H1 Antigen - immunology Animals Phagocytes - microbiology CD8-Positive T-Lymphocytes - drug effects Dogs Leishmania infantum - immunology Oxidative Stress - drug effects CD8-Positive T-Lymphocytes - immunology Programmed Cell Death 1 Receptor - genetics CD4-Positive T-Lymphocytes - drug effects

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