RRC ID 47496
Author Iborra S, Martínez-López M, Cueto FJ, Conde-Garrosa R, Del Fresno C, Izquierdo HM, Abram CL, Mori D, Campos-Martín Y, Reguera RM, Kemp B, Yamasaki S, Robinson MJ, Soto M, Lowell CA, Sancho D.
Title Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection.
Journal Immunity
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.
Volume 45(4)
Pages 788-801
Published 2016-10-18
DOI 10.1016/j.immuni.2016.09.012
PII S1074-7613(16)30381-8
PMID 27742545
PMC PMC5074365
MeSH Adaptive Immunity / immunology* Animals CD11c Antigen / immunology Cell Differentiation / immunology Cell Line, Tumor Dendritic Cells / immunology* Immunoreceptor Tyrosine-Based Activation Motif / immunology* Lectins, C-Type / immunology* Leishmania major / immunology* Membrane Proteins / immunology* Mice Mice, Inbred C57BL Mice, Transgenic Protein Tyrosine Phosphatase, Non-Receptor Type 6 / immunology Receptors, Fc / immunology Signal Transduction / immunology*
IF 22.553
Times Cited 40
DNA material CSII-CMV-MCS-IRES2-Bsd (RDB04385) pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393).