Programmed Death 1–Mediated T Cell Exhaustion during Visceral Leishmaniasis Impairs Phagocyte Function

Journal of Immunology - Tập 191 Số 11 - Trang 5542-5550 - 2013
Kevin J. Esch1, Rachel Juelsgaard1, Pedro Martı́nez1, Douglas E. Jones1, Christine A. Petersen1
1Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, IA 50011

Tóm tắt

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.

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Journal of Immunology

Tập 191 Số 11

5542-5550

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