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.
authors.affiliation: Immunobiology Laboratory, Fundación Centro Nacional de Investigaciones Cardiovasculares "Carlos III" (CNIC), Melchor Fernández Almagro 3, Madrid 28029, Spain; Departamento de Biología Molecular Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, Madrid 28049, Spain. Electronic address: siborra@cnic.es.
authors.forename: Salvador
authors.initials: S
authors.lastname: Iborra
authors.affiliation: Immunobiology Laboratory, Fundación Centro Nacional de Investigaciones Cardiovasculares "Carlos III" (CNIC), Melchor Fernández Almagro 3, Madrid 28029, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Martínez-López
authors.affiliation: Immunobiology Laboratory, Fundación Centro Nacional de Investigaciones Cardiovasculares "Carlos III" (CNIC), Melchor Fernández Almagro 3, Madrid 28029, Spain; Department of Biochemistry, Faculty of Medicine, Universidad Autónoma de Madrid, Calle Arzobispo Morcillo 4, Madrid 28029, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Cueto
authors.affiliation: Immunobiology Laboratory, Fundación Centro Nacional de Investigaciones Cardiovasculares "Carlos III" (CNIC), Melchor Fernández Almagro 3, Madrid 28029, Spain.
authors.forename: Ruth
authors.initials: R
authors.lastname: Conde-Garrosa
authors.affiliation: Immunobiology Laboratory, Fundación Centro Nacional de Investigaciones Cardiovasculares "Carlos III" (CNIC), Melchor Fernández Almagro 3, Madrid 28029, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Del Fresno
authors.affiliation: Immunobiology Laboratory, Fundación Centro Nacional de Investigaciones Cardiovasculares "Carlos III" (CNIC), Melchor Fernández Almagro 3, Madrid 28029, Spain.
authors.forename: Helena M
authors.initials: HM
authors.lastname: Izquierdo
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Abram
authors.affiliation: Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Mori
authors.affiliation: Servicio Anatomía Patológica, Hospital Virgen de la Salud, Avenida de Barber, 30, Toledo 45004, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Campos-Martín
authors.affiliation: Departamento de Ciencias Biomédicas, Universidad de León, Facultad de Veterinaria Campus de Vegazana s/n, León 24071, Spain.
authors.forename: Rosa María
authors.initials: RM
authors.lastname: Reguera
authors.affiliation: Medimmune, Granta Park, Cambridge, CB21 6GH, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kemp
authors.affiliation: Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Yamasaki
authors.affiliation: Medimmune, Granta Park, Cambridge, CB21 6GH, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Robinson
authors.affiliation: Departamento de Biología Molecular Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, Madrid 28049, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Soto
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.affiliation: Immunobiology Laboratory, Fundación Centro Nacional de Investigaciones Cardiovasculares "Carlos III" (CNIC), Melchor Fernández Almagro 3, Madrid 28029, Spain. Electronic address: dsancho@cnic.es.
authors.forename: David
authors.initials: D
authors.lastname: Sancho
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D039521:CD11c Antigen / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D061625:Immunoreceptor Tyrosine-Based Activation Motif / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology*; D018320:Leishmania major / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000276:immunology; D011961:Receptors, Fc / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D039521:CD11c Antigen; C113583:Clecsf8 protein, mouse; D037181:Lectins, C-Type; D008565:Membrane Proteins; D011961:Receptors, Fc; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6