Tocheva Anna S, Mansour Salah, Holt Tristan G H, Jones Samuel, Chancellor Andrew, Sanderson Joseph P, Eren Efrem, Elliott Tim J, Holt Richard I G, Gadola Stephan D
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;
Department of Medicine, New York University School of Medicine, New York, NY 10016.
J Immunol. 2017 Feb 15;198(4):1452-1459. doi: 10.4049/jimmunol.1600255. Epub 2017 Jan 6.
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.
健康人体内的不变自然杀伤T细胞（iNKT细胞）表达的iNKT-TCR对CD1d的亲和力差异很大，这表明高亲和力和低亲和力的iNKT克隆在免疫调节中具有不同作用。然而，这种异质性的功能意义尚未确定。先前已在包括人类1型糖尿病在内的不同自身免疫性疾病中证明了iNKT反应的功能异常，但它们与iNKT克隆库变化的关系尚未得到探讨。在本研究中，我们直接比较了近期发病的1型糖尿病患者与年龄和性别匹配的健康对照在iNKT-TCR亲和力和细胞因子产生方面的iNKT克隆库。我们的结果表明，1型糖尿病患者的iNKT克隆库中表达高亲和力iNKT-TCR的克隆选择性丧失。此外，1型糖尿病患者克隆性iNKT库中的这种偏差与抗原刺激的低亲和力iNKT克隆中GM-CSF、IL-4和IL-13细胞因子分泌增加有关。因此，在1型糖尿病的早期阶段，克隆性iNKT库的定性变化就已经确立，这有可能影响这一高度保守的T细胞群体的调节功能。这些发现可能为未来开发旨在恢复1型糖尿病免疫耐受的基于iNKT的疗法提供理论依据。
