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2018 ; 86
(6
): ä Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
PDL-1 Blockade Prevents T Cell Exhaustion, Inhibits Autophagy, and Promotes
Clearance of Leishmania donovani
#MMPMID29610255
Habib S
; El Andaloussi A
; Elmasry K
; Handoussa A
; Azab M
; Elsawey A
; Al-Hendy A
; Ismail N
Infect Immun
2018[Jun]; 86
(6
): ä PMID29610255
show ga
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.
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