Leishmania Parasites Drive PD-L1 Expression in Mice and Human Neutrophils With Suppressor Capacity

Abstract

Neutrophils play an important role in the outcome of leishmaniasis, contributing either to exacerbating or controlling the progression of infection, a dual effect whose underlying mechanisms are not clear. We recently reported that CD4⁺ and CD8⁺ T cells, and dendritic cells of <i>Leishmania amazonensis-</i>infected mice present high expression of PD-1 and PD-L1, respectively. Given that the PD-1/PD-L1 interaction may promote cellular dysfunction, and that neutrophils could interact with T cells during infection, we investigated here the levels of PD-L1 in neutrophils exposed to <i>Leishmania</i> parasites. We found that both, promastigotes and amastigotes of <i>L. amazonensis</i> induced the expression of PD-L1 in the human and murine neutrophils that internalized these parasites <i>in vitro</i>. PD-L1-expressing neutrophils were also observed in the ear lesions and the draining lymph nodes of <i>L. amazonensis</i>-infected mice, assessed through cell cytometry and intravital microscopy. Moreover, expression of PD-L1 progressively increased in neutrophils from ear lesions as the disease evolved to the chronic phase. Co-culture of infected neutrophils with <i>in vitro</i> activated CD8⁺ T cells inhibits IFN-γ production by a mechanism dependent on PD-1 and PD-L1. Importantly, we demonstrated that <i>in vitro</i> infection of human neutrophils by <i>L braziliensis</i> induced PD-L1⁺ expression and also PD-L1⁺ neutrophils were detected in the lesions of patients with cutaneous leishmaniasis. Taken together, these findings suggest that the <i>Leishmania</i> parasite increases the expression of PD-L1 in neutrophils with suppressor capacity, which could favor the parasite survival through impairing the immune response.