Open AccessThe role of PD‐1 in regulation of macrophage apoptosis and its subversion by Leishmania donovani
Author(s) -
Roy Shalini,
Gupta Purnima,
Palit Shreyasi,
Basu Moumita,
Ukil Anindita,
Das Pijush K
Publication year - 2017
Publication title -
clinical and translational immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.321
H-Index - 34
ISSN - 2050-0068
DOI - 10.1038/cti.2017.12
Subject(s) - leishmania donovani , apoptosis , macrophage , protein kinase b , biology , microbiology and biotechnology , phosphorylation , pi3k/akt/mtor pathway , signal transduction , chemistry , immunology , biochemistry , leishmaniasis , in vitro , visceral leishmaniasis
Programmed death‐1 receptor (PD‐1) expressed in many immune cells is known to trigger T‐cell exhaustion but the significance of macrophage‐associated PD‐1 in relevance to macrophage apoptosis is not known. This study is aimed to delineate whether PD‐1 pathway has any role in eliciting macrophage apoptosis and, if so, then how the intra‐macrophage parasite, Leishmania donovani modulates PD‐1 pathway for protecting its niche. Resting macrophages when treated with H 2 O 2 showed increased PD‐1 expression and apoptosis, which was further enhanced on PD‐1 agonist treatment. The administration of either PD‐1 receptor or PD‐1 ligand‐blocking antibodies reversed the process thus documenting the involvement of PD‐1 in macrophage apoptosis. On the contrary, L. donovani ‐infected macrophages showed decreased PD‐1 expression concurrent with inhibition of apoptosis. The activation of PD‐1 pathway was found to negatively regulate the phosphorylation of pro‐survival AKT, which was reversed during infection. Infection‐induced PD‐1 downregulation led to the activation of AKT resulting in phosphorylation and subsequent inhibition of proapoptotic protein BAD. Strong association of SHP2 (a SH2‐containing ubiquitously expressed tyrosine‐specific protein phosphatase) with PD‐1 along with AKT deactivation observed in H 2 O 2 ‐treated macrophages was reversed by L. donovani infection. Kinetic analysis coupled with inhibitor‐based approach and knockdown experiments demonstrated that L . donovani infection actively downregulated the PD‐1 by deactivating NFATc1 as revealed by its reduced nuclear translocation. The study thus elucidates the detailed mechanism of the role of PD‐1 in macrophage apoptosis and its negative modulation by Leishmania for their intracellular survival.