title: Structural and Functional Changes of the Invariant NKT Clonal Repertoire in Early Rheumatoid Arthritis.
abstract: Invariant NKT cells (iNKT) are potent immunoregulatory T cells that recognize CD1d via a semi-invariant TCR (iNKT-TCR). Despite the knowledge of a defective iNKT pool in several autoimmune conditions, including rheumatoid arthritis (RA), a clear understanding of the intrinsic mechanisms, including qualitative and structural changes of the human iNKT repertoire at the earlier stages of autoimmune disease, is lacking. In this study, we compared the structure and function of the iNKT repertoire in early RA patients with age- and gender-matched controls. We analyzed the phenotype and function of the ex vivo iNKT repertoire as well as CD1d Ag presentation, combined with analyses of a large panel of ex vivo sorted iNKT clones. We show that circulating iNKTs were reduced in early RA, and their frequency was inversely correlated to disease activity score 28. Proliferative iNKT responses were defective in early RA, independent of CD1d function. Functional iNKT alterations were associated with a skewed iNKT-TCR repertoire with a selective reduction of high-affinity iNKT clones in early RA. Furthermore, high-affinity iNKTs in early RA exhibited an altered functional Th profile with Th1- or Th2-like phenotype, in treatment-naive and treated patients, respectively, compared with Th0-like Th profiles exhibited by high-affinity iNKTs in controls. To our knowledge, this is the first study to provide a mechanism for the intrinsic qualitative defects of the circulating iNKT clonal repertoire in early RA, demonstrating defects of iNKTs bearing high-affinity TCRs. These defects may contribute to immune dysregulation, and our findings could be exploited for future therapeutic intervention.
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom; Institute for Life Sciences, University of Southampton, Southampton SO16 6YD, United Kingdom; Stephan.gadola@novartis.com s.mansour@soton.ac.uk.
authors.forename: Salah
authors.initials: S
authors.lastname: Mansour
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom;
authors.forename: Anna S
authors.initials: AS
authors.lastname: Tocheva
authors.affiliation: Adaptimmune, Abingdon OX14 4RY, United Kingdom;
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Sanderson
authors.affiliation: Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton SO16 6YD, United Kingdom; National Institute for Health Research Wellcome Trust Clinical Research Facility, University of Southampton, Southampton SO16 6YD, United Kingdom;
authors.forename: Lyndsey M
authors.initials: LM
authors.lastname: Goulston
authors.affiliation: National Institute for Health Research Wellcome Trust Clinical Research Facility, University of Southampton, Southampton SO16 6YD, United Kingdom;
authors.forename: Helen
authors.initials: H
authors.lastname: Platten
authors.affiliation: National Institute for Health Research Wellcome Trust Clinical Research Facility, University of Southampton, Southampton SO16 6YD, United Kingdom;
authors.forename: Lina
authors.initials: L
authors.lastname: Serhal
authors.affiliation: Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton SO16 6YD, United Kingdom;
authors.forename: Camille
authors.initials: C
authors.lastname: Parsons
authors.affiliation: Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton SO16 6YD, United Kingdom; National Institute for Health Research Wellcome Trust Clinical Research Facility, University of Southampton, Southampton SO16 6YD, United Kingdom;
authors.forename: Mark H
authors.initials: MH
authors.lastname: Edwards
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom; Institute for Life Sciences, University of Southampton, Southampton SO16 6YD, United Kingdom;
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Woelk
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom; Institute for Life Sciences, University of Southampton, Southampton SO16 6YD, United Kingdom;
authors.forename: Paul T
authors.initials: PT
authors.lastname: Elkington
authors.affiliation: Institute for Life Sciences, University of Southampton, Southampton SO16 6YD, United Kingdom; Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom;
authors.forename: Tim
authors.initials: T
authors.lastname: Elliott
authors.affiliation: Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton SO16 6YD, United Kingdom; National Institute for Health Research Wellcome Trust Clinical Research Facility, University of Southampton, Southampton SO16 6YD, United Kingdom; Oxford National Institute for Health Research Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7HE, United Kingdom; and.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Cooper
authors.affiliation: Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton SO16 6YD, United Kingdom; National Institute for Health Research Wellcome Trust Clinical Research Facility, University of Southampton, Southampton SO16 6YD, United Kingdom; Oxford National Institute for Health Research Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7HE, United Kingdom; and.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Edwards
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom; National Institute for Health Research Wellcome Trust Clinical Research Facility, University of Southampton, Southampton SO16 6YD, United Kingdom; Novartis Institutes of Biomedical Research, 4002 Basel, Switzerland Stephan.gadola@novartis.com s.mansour@soton.ac.uk.
authors.forename: Stephan D
authors.initials: SD
authors.lastname: Gadola
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D055610:Antigens, CD1d / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D017637:Clonal Deletion; D002999:Clone Cells; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055611:Natural Killer T-Cells / Q000276:immunology*; D037182:T-Cell Antigen Receptor Specificity; D058408:Th1-Th2 Balance; D055815:Young Adult
chemical_list: D055610:Antigens, CD1d; D016207:Cytokines