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

2 Citations (Scopus)

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
StatePublished - Jun 1 2018

Fingerprint

Leishmania donovani
Visceral Leishmaniasis
Autophagy
T-Lymphocytes
Parasites
Immunity
Th1 Cells
Microtubule-Associated Proteins
Leishmania
Cellular Immunity
Interleukin-10
Light
Costs and Cost Analysis
Food
Antibodies
Therapeutics
Infection

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

PDL-1 blockade prevents T cell exhaustion, inhibits autophagy, and promotes clearance of Leishmania donovani. / Habib, Samar; El Andaloussi, Abdeljabar; Elmasry, Khaled; Handoussa, Aya; Azab, Manar; Elsawey, Aliaa; Al-Hendy, Ayman; Ismail, Nahed.

In: Infection and Immunity, Vol. 86, No. 6, e00019-18, 01.06.2018.

Research output: Contribution to journalArticle

Habib, S, El Andaloussi, A, Elmasry, K, Handoussa, A, Azab, M, Elsawey, A, Al-Hendy, A & Ismail, N 2018, 'PDL-1 blockade prevents T cell exhaustion, inhibits autophagy, and promotes clearance of Leishmania donovani', Infection and Immunity, vol. 86, no. 6, e00019-18. https://doi.org/10.1128/IAI.00019-18
Habib, Samar ; El Andaloussi, Abdeljabar ; Elmasry, Khaled ; Handoussa, Aya ; Azab, Manar ; Elsawey, Aliaa ; Al-Hendy, Ayman ; Ismail, Nahed. / PDL-1 blockade prevents T cell exhaustion, inhibits autophagy, and promotes clearance of Leishmania donovani. In: Infection and Immunity. 2018 ; Vol. 86, No. 6.
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