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

Abstract

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 signaling 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. Mechanistically, PDL-1 blocking inhibited autophagy, a cellular degradation process hijacked by Leishmania to acquire host cell nutrients for their survival. Inhibition of autophagy was marked by decreased lipidation of microtubule-associated protein 1 light chain 3, a marker of autophagosome formation, and P62 accumulation. Together, 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.

Immunotherapy of alveolar echinococcosis via PD‐1/PD‐L1 immune checkpoint blockade in mice

“…With regard to helminth infection, it was shown that cestode Taenia crassiceps infections in mice induce macrophages alternatively activated with strong suppressive activity involving the PD‐1/PD‐L1 pathway . Blockade of the PD‐1/PD‐L1 pathway during infections with certain pathogens such as Toxoplasma restored exhausted CD8 + T cell response, and promoted brain leucocyte infiltration and diminishes cyst burden in another mouse infection model . It was also shown that blocking PD‐L1 signalling in Leishmania donovani ‐infected mice resulted in restoration of protective type 1 responses by both CD4 + and CD8 + T cells, which resulted in a significant decrease in the parasitic burden .…”

The Effect of Iodium 30c on Experimental Visceral Leishmaniasis

“…41 Similarly, experiments conducted on the blocking of PDL-1 accessory proteins expressed on the surface of T cells in inbred BALB/c mice led to a significant reduction in the parasite load and increased the levels of protective type CD4 þ and CD8 þ T cell-mediated immune response. 42 Histopathology VL, a distinctive immunosuppressive disease, is characterised by severe hepatomegaly and splenomegaly during the acute phase of illness. A successful treatment not only shifts the immune response toward the adaptive type but also preserves normal architecture of the severely affected organs.…”

The Interplay of Host Autophagy and Eukaryotic Pathogens

“…Single bilayers positive of LC3 seem to surround apoptotic Leishmania major with the consequence of dampening the parasite-directed CD4 T cell response ( Crauwels et al, 2015 ). Reducing T cell exhaustion by blocking PD1-L signaling inhibited autophagy and reduced Leishmania donovani burden ( Habib et al, 2018 ).…”