title: Human autoreactive T cells recognize CD1b and phospholipids.
abstract: In contrast with the common detection of T cells that recognize MHC, CD1a, CD1c, or CD1d proteins, CD1b autoreactive T cells have been difficult to isolate in humans. Here we report the development of polyvalent complexes of CD1b proteins and carbohydrate backbones (dextramers) and their use in identifying CD1b autoreactive T cells from human donors. Activation is mediated by αβ T-cell receptors (TCRs) binding to CD1b-phospholipid complexes, which is sufficient to activate autoreactive responses to CD1b-expressing cells. Using mass spectrometry and T-cell responses to scan through the major classes of phospholipids, we identified phosphatidylglycerol (PG) as the immunodominant lipid antigen. T cells did not discriminate the chemical differences that distinguish mammalian PG from bacterial PG. Whereas most models of T-cell recognition emphasize TCR discrimination of differing self and foreign structures, CD1b autoreactive T cells recognize lipids with dual self and foreign origin. PG is rare in the cellular membranes that carry CD1b proteins. However, bacteria and mitochondria are rich in PG, so these data point to a more general mechanism of immune detection of infection- or stress-associated lipids.
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, The Netherlands; bmoody@partners.org mbrenner@partners.org i.vanrhijn@uu.nl.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Van Rhijn
authors.affiliation: Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, The Netherlands;
authors.forename: Twan
authors.initials: T
authors.lastname: van Berlo
authors.affiliation: Department of Microbiology & Immunology, Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: Tamara
authors.initials: T
authors.lastname: Hilmenyuk
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Tan-Yun
authors.initials: TY
authors.lastname: Cheng
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Wolf
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Raju V V
authors.initials: RV
authors.lastname: Tatituri
authors.affiliation: Department of Microbiology & Immunology, Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: Adam P
authors.initials: AP
authors.lastname: Uldrich
authors.affiliation: Medical Research Council Human Immunology Unit, Radcliffe Department of Medicine, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom;
authors.forename: Giorgio
authors.initials: G
authors.lastname: Napolitani
authors.affiliation: Medical Research Council Human Immunology Unit, Radcliffe Department of Medicine, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom;
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
authors.affiliation: Emory Vaccine Center, Atlanta, GA 30329;
authors.forename: John D
authors.initials: JD
authors.lastname: Altman
authors.affiliation: Central Veterinary Institute, Wageningen University, 8219 PH Lelystad, The Netherlands;
authors.forename: Peter
authors.initials: P
authors.lastname: Willemsen
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Shouxiong
authors.initials: S
authors.lastname: Huang
authors.affiliation: Infection and Immunity Program, Monash University, Wellington Road, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Wellington Road, Clayton, VIC 3800, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Wellington Road, Clayton, VIC 3800, Australia; Institute of Infection and Immunity, Cardiff University, Cardiff CF10 3XQ, United Kingdom;
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; bmoody@partners.org mbrenner@partners.org i.vanrhijn@uu.nl.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Brenner
authors.affiliation: Department of Microbiology & Immunology, Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: Dale I
authors.initials: DI
authors.lastname: Godfrey
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; bmoody@partners.org mbrenner@partners.org i.vanrhijn@uu.nl.
authors.forename: D Branch
authors.initials: DB
authors.lastname: Moody
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D018949:Antigens, CD1 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020014:K562 Cells; D008213:Lymphocyte Activation / Q000276:immunology; D013058:Mass Spectrometry; D010715:Phosphatidylglycerols / Q000737:chemistry; D010743:Phospholipids / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection
chemical_list: D018949:Antigens, CD1; C419394:CD1b antigen; D010715:Phosphatidylglycerols; D010743:Phospholipids
keywords: CD1b; T cell; dendritic cell; lipid antigen; self-antigen