Leishmania amazonensis infection induces PD-L1 expression on dendritic cells and impairs Th1 responses in vitro and in vivo.

Leishmania amazonensis is an etiological agent of diffuse cutaneous leishmaniasis in South America. In murine models, dysfunctional expansion of effector T cells and Th1 response exhaustion are linked to pathogenesis, while regulatory T cells (Tregs) promote lesion resolution. This study examined the roles of PD-1 and PD-L1 in the immunopathogenesis of L. amazonensis infection in C57BL/6 mice. We found a significant increase in PD-1 and PD-L1 expression in infected tissues, correlating with increased PD-L1+CD11c+ dendritic cells (DCs) and PD-1+CD4+ T cells in draining lymph nodes. Infection of bone marrow-derived DCs (BMDCs) with promastigotes and amastigotes revealed that PD-L1 expression was induced by mTOR, partially by STAT3, PI3K, and MAPK. Infected BMDCs in vitro inhibited Th1 cell expansion compared to non-infected BMDCs. In vivo experiments showed that PD-L1-/- mice exhibited increased Th1 responses, reduced lesion sizes, and lower parasite loads. These results suggest a non-protective role for PD-1/PD-L1 signaling in regulating local immune responses during L. amazonensis infection, providing new insights into immune regulation in New World cutaneous leishmaniasis.