PDL-1 Blockade Prevents T Cell Exhaustion, Inhibits Autophagy, and Promotes Clearance of Leishmania donovani

Leishmania donovani is a causative pathogen of potentially fatal visceral leishmaniasis (VL). Therapeutic agents are available; however, their use is limited because of high cost, serious side effects, and development of antimicrobial resistance. Protective immunity against VL depends on CD4(+) Th1 cell-mediated immunity. Studies have shown that progression of VL is due to exhaustion of T cells; however, the mechanism involved is not clearly understood. Here, we examined the role of PD1/PDL-1 in the pathogenesis of VL by using a murine model of VL. Our data indicate that L. donovani is able to elicit initial expansion of gamma interferon-producing CD4(+) Th1 and CD8(+) T cells at day 7 postinfection (p.i.); however, the frequency of those cells and inflammatory response decreased at day 21 p.i., despite persistence of parasites. Persistent infection-induced expansion of interleukin-10(+) FOXP3(+) Treg and CD4(+) and CD8(+) T cells expressing PD1. Blocking of PDL-1 signal-ing in vivo resulted in restoration of protective type 1 responses by both CD4(+) and CD8(+) T cells, which resulted in a significant decrease in the parasite burden. Mechan-istically, PDL-1 blocking inhibited autophagy, a cellular degradation process hi-jacked by Leishmania to acquire host cell nutrients for their survival. Inhibition of au-tophagy was marked by decreased lipidation of microtubule-associated protein 1 light chain 3, a marker of autophagosome formation, and P62 accumulation. To-gether, our findings show for the first time that anti-PDL-1 antibody is an effective therapeutic approach for restoration of effector arms of protective immunity against VL and subsequent parasite clearance.