title: The Clonal Invariant NKT Cell Repertoire in People with Type 1 Diabetes Is Characterized by a Loss of Clones Expressing High-Affinity TCRs.
abstract: Invariant NKT (iNKT) cells in healthy people express iNKT-TCRs with widely varying affinities for CD1d, suggesting different roles for high- and low-affinity iNKT clones in immune regulation. However, the functional implications of this heterogeneity have not yet been determined. Functionally aberrant iNKT responses have been previously demonstrated in different autoimmune diseases, including human type 1 diabetes, but their relationship to changes in the iNKT clonal repertoire have not been addressed. In this study, we directly compared the clonal iNKT repertoire of people with recent onset type 1 diabetes and age- and gender-matched healthy controls with regard to iNKT-TCR affinity and cytokine production. Our results demonstrate a selective loss of clones expressing high-affinity iNKT-TCRs from the iNKT repertoire of people with type 1 diabetes. Furthermore, this bias in the clonal iNKT repertoire in type 1 diabetes was associated with increased GM-CSF, IL-4, and IL-13 cytokine secretion among Ag-stimulated low-affinity iNKT clones. Thus, qualitative changes of the clonal iNKT repertoire with the potential to affect the regulatory function of this highly conserved T cell population are already established at the early stages in type 1 diabetes. These findings may inform future rationales for the development of iNKT-based therapies aiming to restore immune tolerance in type 1 diabetes.
authors.affiliation: Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton National Health Service Foundation Trust, Southampton SO17 1BJ, United Kingdom; Anna.Tocheva@nyumc.org sgadola@gmail.com.|Department of Medicine, New York University School of Medicine, New York, NY 10016.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Tocheva
authors.affiliation: Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton National Health Service Foundation Trust, Southampton SO17 1BJ, United Kingdom.|Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Salah
authors.initials: S
authors.lastname: Mansour
authors.affiliation: Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton National Health Service Foundation Trust, Southampton SO17 1BJ, United Kingdom.
authors.forename: Tristan G H
authors.identifier: 0000-0002-6369-0286
authors.initials: TG
authors.lastname: Holt
authors.affiliation: Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton National Health Service Foundation Trust, Southampton SO17 1BJ, United Kingdom.
authors.forename: Samuel
authors.initials: S
authors.lastname: Jones
authors.affiliation: Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton National Health Service Foundation Trust, Southampton SO17 1BJ, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chancellor
authors.affiliation: AdaptImmune Ltd., Abingdon OX14 4RY, United Kingdom.
authors.forename: Joseph P
authors.identifier: 0000-0002-1206-8833
authors.initials: JP
authors.lastname: Sanderson
authors.affiliation: Department of Clinical Immunology, University Hospital Southampton National Health Service Foundation Trust, Southampton SO17 1BJ, United Kingdom.
authors.forename: Efrem
authors.identifier: 0000-0002-7815-6094
authors.initials: E
authors.lastname: Eren
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Elliott
authors.affiliation: Human Development and Health, Faculty of Medicine, University of Southampton, University Hospital Southampton National Health Service Foundation Trust, Southampton SO17 1BJ, United Kingdom; and.
authors.forename: Richard I G
authors.initials: RI
authors.lastname: Holt
authors.affiliation: Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton National Health Service Foundation Trust, Southampton SO17 1BJ, United Kingdom; Anna.Tocheva@nyumc.org sgadola@gmail.com.|Translational medicine, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland.
authors.forename: Stephan D
authors.initials: SD
authors.lastname: Gadola
mesh_terms: D000293:Adolescent; D000328:Adult; D055610:Antigens, CD1d / Q000235:genetics; D002999:Clone Cells; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000503:physiopathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D018793:Interleukin-13 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D055611:Natural Killer T-Cells / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency / Q000235:genetics* / Q000276:immunology*; D055815:Young Adult
chemical_list: D055610:Antigens, CD1d; C526877:CD1D protein, human; D018793:Interleukin-13; D011948:Receptors, Antigen, T-Cell; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor