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

Salvador Iborra, María Martínez-López, Francisco J. Cueto, Ruth Conde-Garrosa, Carlos Del Fresno, Helena M. Izquierdo, Clare L. Abram, Daiki Mori, Yolanda Campos-Martín, Rosa María Reguera, Benjamin Kemp, Sho Yamasaki, Matthew J. Robinson, Manuel Soto, Clifford A. Lowell, David Sancho

    Research output: Contribution to journalArticle

    35 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)788-801
    Number of pages14
    JournalImmunity
    Volume45
    Issue number4
    DOIs
    Publication statusPublished - Oct 18 2016

      Fingerprint

    All Science Journal Classification (ASJC) codes

    • Immunology and Allergy
    • Immunology
    • Infectious Diseases

    Cite this

    Iborra, S., Martínez-López, M., Cueto, F. J., Conde-Garrosa, R., Del Fresno, C., Izquierdo, H. M., ... Sancho, D. (2016). Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection. Immunity, 45(4), 788-801. https://doi.org/10.1016/j.immuni.2016.09.012