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primary topic: TIM-3 increases the abundance of type-2 dendritic cells during Leishmania donovani infection by enhancing IL-10 production via STAT3

TIM-3 increases the abundance of type-2 dendritic cells during Leishmania donovani infection by enhancing IL-10 production via STAT3
type: AcademicArticle
type: Article
abstract: The outcome of the disease visceral leishmaniasis (VL), caused by Leishmania donovani (LD), largely relies on the relative dominance of host-protective type-1 T helper (Th1) cell response versus disease-promoting type-2 T helper (Th2) cell response. The Th1 and Th2 responses, in turn, are believed to be elicited by type-1 conventional dendritic cells (cDC1) and type-2 conventional DCs (cDC2), respectively. However, it is still unknown which DC subtype (cDC1 or cDC2) predominates during chronic LD infection and the molecular mechanism governing such occurrence. Here we report that in chronically infected mice, the splenic cDC1-cDC2 balance shifted toward the cDC2 subtype and that the receptor T cell immunoglobulin and mucin protein-3 (TIM-3) expressed by DCs played a key role in mediating this effect. Transfer of TIM-3-silenced DCs in fact prevented the predominance of the cDC2 subtype in mice with chronic LD infection. We also found that LD actually upregulated TIM-3 expression on DCs by triggering a TIM-3-mediated signaling pathway STAT3 (signal transducer and activator of transcription 3)→interleukin (IL)-10→c-Src→transcription factors Ets1, Ets2, USF1, and USF2. Notably, TIM-3 promoted STAT3 activation via a non-receptor tyrosine kinase Btk. Adoptive transfer experiments further demonstrated a critical role for STAT3-driven TIM-3 upregulation on DCs in increasing cDC2 abundance in chronically infected mice, which ultimately aided disease pathogenesis by augmenting Th2 responses. These findings document a new immunoregulatory mechanism contributing to disease pathology during LD infection and define TIM-3 as a key mediator of this process.
date: 2023-05-18
volume: 14
issue: 5
is part of: Cell death & disease
status: peerReviewed
status: published
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository
subject: QR Microbiology

Nature
type: Organization

Cell death & disease
type: Collection
issn: 20414889

Manish Mishra
type: Person
given name: Manish
family name: Mishra

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

Sandeep Kumar
type: Person
given name: Sandeep
family name: Kumar

Manisha Yadav
type: Person
given name: Manisha
family name: Yadav

Raj Kumar
type: Person
given name: Raj
family name: Kumar

HTML Summary of #3093 TIM-3 increases the abundance of type-2 dendritic cells during Leishmania donovani infection by enhancing IL-10 production via STAT3
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primary topic: TIM-3 increases the abundance of type-2 dendritic cells during Leishmania donovani infection by enhancing IL-10 production via STAT3

QR Microbiology
type: Concept