title: Bee venom processes human skin lipids for presentation by CD1a.
abstract: Venoms frequently co-opt host immune responses, so study of their mode of action can provide insight into novel inflammatory pathways. Using bee and wasp venom responses as a model system, we investigated whether venoms contain CD1-presented antigens. Here, we show that venoms activate human T cells via CD1a proteins. Whereas CD1 proteins typically present lipids, chromatographic separation of venoms unexpectedly showed that stimulatory factors partition into protein-containing fractions. This finding was explained by demonstrating that bee venom-derived phospholipase A2 (PLA2) activates T cells through generation of small neoantigens, such as free fatty acids and lysophospholipids, from common phosphodiacylglycerides. Patient studies showed that injected PLA2 generates lysophospholipids within human skin in vivo, and polyclonal T cell responses are dependent on CD1a protein and PLA2. These findings support a previously unknown skin immune response based on T cell recognition of CD1a proteins and lipid neoantigen generated in vivo by phospholipases. The findings have implications for skin barrier sensing by T cells and mechanisms underlying phospholipase-dependent inflammatory skin disease.
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02114.
authors.forename: Elvire A
authors.initials: EA
authors.lastname: Bourgeois
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine and University of Oxford NIHR Biomedical Research Centre, Oxford, Oxfordshire OX3 9DS, England, UK MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine and University of Oxford NIHR Biomedical Research Centre, Oxford, Oxfordshire OX3 9DS, England, UK.
authors.forename: Sumithra
authors.initials: S
authors.lastname: Subramaniam
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02114.
authors.forename: Tan-Yun
authors.initials: TY
authors.lastname: Cheng
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02114.
authors.forename: Annemieke
authors.initials: A
authors.lastname: De Jong
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02114.
authors.forename: Emilie
authors.initials: E
authors.lastname: Layre
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02114.
authors.forename: Dalam
authors.initials: D
authors.lastname: Ly
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine and University of Oxford NIHR Biomedical Research Centre, Oxford, Oxfordshire OX3 9DS, England, UK MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine and University of Oxford NIHR Biomedical Research Centre, Oxford, Oxfordshire OX3 9DS, England, UK.
authors.forename: Maryam
authors.initials: M
authors.lastname: Salimi
authors.affiliation: Division of Dermatology, David Geffen School of Medicine, Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095 Division of Dermatology, David Geffen School of Medicine, Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095.
authors.forename: Annaliza
authors.initials: A
authors.lastname: Legaspi
authors.affiliation: Division of Dermatology, David Geffen School of Medicine, Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095 Division of Dermatology, David Geffen School of Medicine, Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine and University of Oxford NIHR Biomedical Research Centre, Oxford, Oxfordshire OX3 9DS, England, UK MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine and University of Oxford NIHR Biomedical Research Centre, Oxford, Oxfordshire OX3 9DS, England, UK.
authors.forename: Mariolina
authors.initials: M
authors.lastname: Salio
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine and University of Oxford NIHR Biomedical Research Centre, Oxford, Oxfordshire OX3 9DS, England, UK MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine and University of Oxford NIHR Biomedical Research Centre, Oxford, Oxfordshire OX3 9DS, England, UK.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02114 bmoody@partners.org graham.ogg@ndm.ox.ac.uk.
authors.forename: D Branch
authors.initials: DB
authors.lastname: Moody
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine and University of Oxford NIHR Biomedical Research Centre, Oxford, Oxfordshire OX3 9DS, England, UK MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine and University of Oxford NIHR Biomedical Research Centre, Oxford, Oxfordshire OX3 9DS, England, UK bmoody@partners.org graham.ogg@ndm.ox.ac.uk.
authors.forename: Graham
authors.initials: G
authors.lastname: Ogg
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D018949:Antigens, CD1 / Q000276:immunology* / Q000378:metabolism; D001514:Bee Venoms / Q000737:chemistry / Q000276:immunology*; D002460:Cell Line; D005227:Fatty Acids / Q000096:biosynthesis; D006801:Humans; D008024:Ligands; D008055:Lipids / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008246:Lysophospholipids / Q000378:metabolism; D054467:Phospholipases A2 / Q000276:immunology; D012867:Skin / Q000276:immunology* / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D018949:Antigens, CD1; D001514:Bee Venoms; C419393:CD1a antigen; D005227:Fatty Acids; D008024:Ligands; D008055:Lipids; D008246:Lysophospholipids; D054467:Phospholipases A2