PDL-1 blockade prevents T cell exhaustion, inhibits autophagy, and promotes clearance of Leishmania donovani

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

Research output: Contribution to journalArticle

6 Scopus citations

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 interferonproducing 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.

Original languageEnglish (US)
Article numbere00019-18
JournalInfection and Immunity
Volume86
Issue number6
DOIs
Publication statusPublished - Jun 1 2018

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Keywords

  • Autophagy
  • Immunity
  • Immunotherapy
  • Leishmania donovani
  • PD1
  • PDL-1
  • T cell exhaustion
  • T cell immunity

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

Cite this

Habib, S., El Andaloussi, A., Elmasry, K., Handoussa, A., Azab, M., Elsawey, A., ... Ismail, N. (2018). PDL-1 blockade prevents T cell exhaustion, inhibits autophagy, and promotes clearance of Leishmania donovani. Infection and Immunity, 86(6), [e00019-18]. https://doi.org/10.1128/IAI.00019-18