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primary topic: Leishmania donovani Impedes Antileishmanial Immunity by Suppressing Dendritic Cells via the TIM-3 Receptor

Leishmania donovani Impedes Antileishmanial Immunity by Suppressing Dendritic Cells via the TIM-3 Receptor
type: AcademicArticle
type: Article
abstract: An immunological hallmark of visceral leishmaniasis (VL), caused by Leishmania donovani, is profound immunosuppression. However, the molecular basis for this immune dysfunction has remained ill defined. Since dendritic cells (DCs) normally initiate antileishmanial immune responses, we investigated whether DCs are dysregulated during L. donovani infection and assessed its role in immunosuppression. Accordingly, we determined the regulatory effect of L. donovani on DCs. Notably, it is still unclear whether L. donovani activates or suppresses DCs. In addition, the molecular mechanism and the relevant receptor (or receptors) mediating the immunoregulatory effect of L. donovani on DCs are largely undefined. Here, we report that L. donovani inhibited DC activation/maturation by transmitting inhibitory signals through the T cell immunoglobulin and mucin protein-3 (TIM-3) receptor and thereby suppressed antileishmanial immune responses. L. donovani in fact triggered TIM-3 phosphorylation in DCs, which in turn recruited and activated a nonreceptor tyrosine kinase, Btk. Btk then inhibited DC activation/maturation by suppressing the NF-κB pathway in an interleukin-10 (IL-10)-dependent manner. Treatment with TIM-3-specific blocking antibody or suppressed expression of TIM-3 or downstream effector Btk made DCs resistant to the inhibitory effects of L. donovani. Adoptive transfer experiments further demonstrated that TIM-3-mediated L. donovani-induced inhibition of DCs plays a crucial role in the suppression of the antileishmanial immune response in vivo. These findings identify TIM-3 as a new regulator of the antileishmanial immune response and demonstrate a unique mechanism for host immunosuppression associated with L. donovani infection. IMPORTANCE Visceral leishmaniasis (VL), a poverty-related disease caused by Leishmania donovani, is ranked by the World Health Organization as the second largest killer parasitic disease in the world. The protective immune response against VL …
date: 2022-08-30
volume: 13
issue: 4
status: peerReviewed
status: published
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository
subject: QR Microbiology

American Society for Microbiology
type: Organization

MBIO
type: Collection

Pradip Sen
type: Person
given name: Pradip
family name: Sen

Sahil Kumar
type: Person
given name: Sahil
family name: Kumar

Md Naushad Akhtar
type: Person
given name: Md Naushad
family name: Akhtar

HTML Summary of #3045 Leishmania donovani Impedes Antileishmanial Immunity by Suppressing Dendritic Cells via the TIM-3 Receptor
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primary topic: Leishmania donovani Impedes Antileishmanial Immunity by Suppressing Dendritic Cells via the TIM-3 Receptor

QR Microbiology
type: Concept