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

  • Kevin J. Esch
    Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, IA 50011
  • Rachel Juelsgaard
    Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, IA 50011
  • Pedro A. Martinez
    Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, IA 50011
  • Douglas E. Jones
    Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, IA 50011
  • Christine A. Petersen
    Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, IA 50011

説明

<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>

収録刊行物

  • The Journal of Immunology

    The Journal of Immunology 191 (11), 5542-5550, 2013-12-01

    The American Association of Immunologists

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