Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells That Dampens Adaptive Immunity to Infection

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2016 Oct 16

PMID 27742545

Citations 47

Authors

Salvador Iborra

Maria Martinez-Lopez

Francisco J Cueto

Ruth Conde-Garrosa

Carlos Del Fresno

Helena M Izquierdo

Clare L Abram

Daiki Mori

Yolanda Campos-Martin

Rosa Maria Reguera

Benjamin Kemp

Sho Yamasaki

Matthew J Robinson

Manuel Soto

Clifford A Lowell

David Sancho

Affiliations

Soon will be listed here.

Abstract

C-type lectin receptors sense a diversity of endogenous and exogenous ligands that may trigger differential responses. Here, we have found that human and mouse Mincle bind to a ligand released by Leishmania, a eukaryote parasite that evades an effective immune response. Mincle-deficient mice had milder dermal pathology and a tenth of the parasite burden compared to wild-type mice after Leishmania major intradermal ear infection. Mincle deficiency enhanced adaptive immunity against the parasite, correlating with increased activation, migration, and priming by Mincle-deficient dendritic cells (DCs). Leishmania triggered a Mincle-dependent inhibitory axis characterized by SHP1 coupling to the FcRγ chain. Selective loss of SHP1 in CD11c cells phenocopies enhanced adaptive immunity to Leishmania. In conclusion, Leishmania shifts Mincle to an inhibitory ITAM (ITAMi) configuration that impairs DC activation. Thus, ITAMi can be exploited for immune evasion by a pathogen and may represent a paradigm for ITAM-coupled receptors sensing self and non-self.

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