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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.

Original publication

DOI

10.4049/jimmunol.1600255

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

02/2017

Volume

198

Pages

1452 - 1459

Addresses

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.

Keywords

Clone Cells, Humans, Diabetes Mellitus, Type 1, Granulocyte-Macrophage Colony-Stimulating Factor, Receptors, Antigen, T-Cell, Interleukin-4, Interleukin-13, Adolescent, Adult, Antigens, CD1d, Natural Killer T-Cells, Young Adult