Authors

Esch KJ, Juelsgaard R, Martinez PA, Jones DE, Petersen CA

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 antigen-specific proliferation and IFNγ production, corresponding to increasing VL symptomatology. Exhaustion was associated with a fourfold 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 antigen stimulation. Antibody block of PD-1 ligand, B7.H1, promoted return of CD4+ and CD8+ T cell function and dramatically increased reactive oxygen species production in co-cultured monocyte-derived phagocytes. As a result, these phagocytes had decreased parasite load. 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 infantumin this important reservoir species.

For the rest of the paper, please visit http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896087/