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, Shou Yamasaki, Matthew J. Robinson, Manuel Soto, Clifford A. Lowell, David Sancho

    Research output: Contribution to journalArticle

    29 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

    Leishmania
    Adaptive Immunity
    Dendritic Cells
    Infection
    Parasites
    Ligands
    C-Type Lectins
    Immune Evasion
    Eukaryota
    Ear
    Pathology

    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

    Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection. / Iborra, Salvador; Martínez-López, María; Cueto, Francisco J.; Conde-Garrosa, Ruth; Del Fresno, Carlos; Izquierdo, Helena M.; Abram, Clare L.; Mori, Daiki; Campos-Martín, Yolanda; Reguera, Rosa María; Kemp, Benjamin; Yamasaki, Shou; Robinson, Matthew J.; Soto, Manuel; Lowell, Clifford A.; Sancho, David.

    In: Immunity, Vol. 45, No. 4, 18.10.2016, p. 788-801.

    Research output: Contribution to journalArticle

    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 2016, 'Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection', Immunity, vol. 45, no. 4, pp. 788-801. https://doi.org/10.1016/j.immuni.2016.09.012
    Iborra, Salvador ; Martínez-López, María ; Cueto, Francisco J. ; Conde-Garrosa, Ruth ; Del Fresno, Carlos ; Izquierdo, Helena M. ; Abram, Clare L. ; Mori, Daiki ; Campos-Martín, Yolanda ; Reguera, Rosa María ; Kemp, Benjamin ; Yamasaki, Shou ; Robinson, Matthew J. ; Soto, Manuel ; Lowell, Clifford A. ; Sancho, David. / Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection. In: Immunity. 2016 ; Vol. 45, No. 4. pp. 788-801.
    @article{b283d6916f4b48c8b9d28b8e1c8a01a1,
    title = "Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection",
    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.",
    author = "Salvador Iborra and Mar{\'i}a Mart{\'i}nez-L{\'o}pez and Cueto, {Francisco J.} and Ruth Conde-Garrosa and {Del Fresno}, Carlos and Izquierdo, {Helena M.} and Abram, {Clare L.} and Daiki Mori and Yolanda Campos-Mart{\'i}n and Reguera, {Rosa Mar{\'i}a} and Benjamin Kemp and Shou Yamasaki and Robinson, {Matthew J.} and Manuel Soto and Lowell, {Clifford A.} and David Sancho",
    year = "2016",
    month = "10",
    day = "18",
    doi = "10.1016/j.immuni.2016.09.012",
    language = "English",
    volume = "45",
    pages = "788--801",
    journal = "Immunity",
    issn = "1074-7613",
    publisher = "Cell Press",
    number = "4",

    }

    TY - JOUR

    T1 - Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection

    AU - Iborra, Salvador

    AU - Martínez-López, María

    AU - Cueto, Francisco J.

    AU - Conde-Garrosa, Ruth

    AU - Del Fresno, Carlos

    AU - Izquierdo, Helena M.

    AU - Abram, Clare L.

    AU - Mori, Daiki

    AU - Campos-Martín, Yolanda

    AU - Reguera, Rosa María

    AU - Kemp, Benjamin

    AU - Yamasaki, Shou

    AU - Robinson, Matthew J.

    AU - Soto, Manuel

    AU - Lowell, Clifford A.

    AU - Sancho, David

    PY - 2016/10/18

    Y1 - 2016/10/18

    N2 - 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.

    AB - 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.

    UR - http://www.scopus.com/inward/record.url?scp=84994879810&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84994879810&partnerID=8YFLogxK

    U2 - 10.1016/j.immuni.2016.09.012

    DO - 10.1016/j.immuni.2016.09.012

    M3 - Article

    VL - 45

    SP - 788

    EP - 801

    JO - Immunity

    JF - Immunity

    SN - 1074-7613

    IS - 4

    ER -