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

Samar Habib,Ayman Al-Hendy,Nahed Ismail,Aya Handoussa,Aliaa Elsawey,Khaled Elmasry,Abdeljabar El Andaloussi,Manar Azab,Judith A Appleton

doi:10.1128/iai.00019-18

Abstract

ABSTRACTLeishmania 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.

Highlights

Leishmania donovani is a causative pathogen of potentially fatal visceral leishmaniasis (VL)
Leishmania is known to exploit the immune mechanisms of the host in order to evade the host immune responses and persist; the mechanism by which L. donovani exploits the immune system is not fully understood
We selected BALB/c mice for our experiments because they are susceptible to L. donovani infection and develop a VL that recapitulates the disease in humans [19]

Summary

Introduction

Leishmania donovani is a causative pathogen of potentially fatal visceral leishmaniasis (VL). Blocking of PDL-1 signaling in vivo resulted in restoration of protective type 1 responses by both CD4ϩ and CD8ϩ T cells, which resulted in a significant decrease in the parasite burden. Control of VL depends on gamma interferon (IFN-␥) production by Th1 CD4ϩ T cells, which promotes protective cell-mediated immunity via several mechanisms, including induction of cytotoxic CD8ϩ T cells that lyse infected cells and activation of macrophage bactericidal functions that clear intracellular parasites [2]. Blockade of the PD1/PDL-1 pathway during infections with certain pathogens such as Toxoplasma and Plasmodium restored exhausted CD8ϩ T and B cell responses, respectively, controlled parasite reactivation, and prevented death in chronically infected animals [15, 16]. The effect of blocking PD1/PDL-1 signaling on CD4ϩ T cell responses during L. donovani infection has not been studied. The interaction between autophagy and the PD1/PDL-1 pathway has not been clearly understood

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Conclusion