Diabetologia ( IF 8.4 ) Pub Date : 2021-08-04 , DOI: 10.1007/s00125-021-05527-y Isabelle Nel 1 , Lucie Beaudoin 1 , Zouriatou Gouda 1 , Camille Rousseau 1 , Pauline Soulard 1 , Matthieu Rouland 1 , Léo Bertrand 1 , Christian Boitard 1, 2 , Etienne Larger 1, 2 , Agnès Lehuen 1
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Aims/hypothesis
Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes expressing an αβ T cell antigen receptor that recognises the MHC-related 1 molecule. MAIT cells are altered in children at risk for and with type 1 diabetes, and mouse model studies have shown MAIT cell involvement in type 1 diabetes development. Since several studies support heterogeneity in type 1 diabetes physiopathology according to the age of individuals, we investigated whether MAIT cells were altered in adults with type 1 diabetes.
Methods
MAIT cell frequency, phenotype and function were analysed by flow cytometry, using fresh peripheral blood from 21 adults with recent-onset type 1 diabetes (2–14 days after disease onset) and 47 adults with long-term disease (>2 years after diagnosis) compared with 55 healthy blood donors. We also separately analysed 17 women with long-term type 1 diabetes and an associated autoimmune disease, compared with 30 healthy women and 27 women with long-term type 1 diabetes.
Results
MAIT cells from adults with recent-onset type 1 diabetes, compared with healthy adult donors, harboured a strongly activated phenotype indicated by an elevated CD25+ MAIT cell frequency. In adults with long-term type 1 diabetes, MAIT cells displayed an activated and exhausted phenotype characterised by high CD25 and programmed cell death 1 (PD1) expression and a decreased production of proinflammatory cytokines, IL-2, IFN-γ and TNF-α. Even though MAIT cells from these patients showed upregulated IL-17 and IL-4 production, the polyfunctionality of MAIT cells was decreased (median 4.8 vs 13.14% of MAIT cells, p < 0.001) and the frequency of MAIT cells producing none of the effector molecules analysed increased (median 34.40 vs 19.30% of MAIT cells, p < 0.01). Several MAIT cell variables correlated with HbA1c level and more particularly in patients with recent-onset type 1 diabetes. In women with long-term type 1 diabetes, MAIT cell alterations were more pronounced in those with an associated autoimmune disease than in those without another autoimmune disease. In women with long-term type 1 diabetes and an associated autoimmune disease, there was an increase in CD69 expression and a decrease in the survival B-cell lymphoma 2 (BCL-2) (p < 0.05) and CD127 (IL-7R) (p < 0.01) marker expression compared with women without a concomitant autoimmune disorder. Concerning effector molecules, TNF-α and granzyme B production by MAIT cells was decreased.
Conclusions/interpretation
Alterations in MAIT cell frequency, phenotype and function were more pronounced in adults with long-term type 1 diabetes compared with adults with recent-onset type 1 diabetes. There were several correlations between MAIT cell variables and clinical characteristics. Moreover, the presence of another autoimmune disease in women with long-term type 1 diabetes further exacerbated MAIT cell alterations. Our results suggest that MAIT cell alterations in adults with type 1 diabetes could be associated with two aspects of the disease: impaired glucose homeostasis; and autoimmunity.
Graphical abstract
中文翻译：
近期和长期 1 型糖尿病患者的 MAIT 细胞改变
目标/假设
粘膜相关不变 T (MAIT) 细胞是先天样 T 淋巴细胞，表达识别 MHC 相关 1 分子的 αβ T 细胞抗原受体。MAIT 细胞在有 1 型糖尿病风险和患有 1 型糖尿病的儿童中发生了改变，小鼠模型研究表明 MAIT 细胞参与了 1 型糖尿病的发展。由于几项研究支持根据个体年龄的 1 型糖尿病病理生理学的异质性，我们研究了 MAIT 细胞是否在 1 型糖尿病成人中发生了改变。
方法
MAIT 细胞频率、表型和功能通过流式细胞术分析，使用来自 21 名新近发病的 1 型糖尿病（发病后 2-14 天）和 47 名患有长期疾病（诊断后 2 年以上）的成年人的新鲜外周血) 与 55 名健康献血者相比。我们还分别分析了 17 名患有长期 1 型糖尿病和相关自身免疫性疾病的女性，以及 30 名健康女性和 27 名患有长期 1 型糖尿病的女性。
结果
与健康的成年供体相比，新近发病的 1 型糖尿病患者的 MAIT 细胞具有由 CD25 + MAIT 细胞频率升高表明的强烈活化表型。在患有长期 1 型糖尿病的成年人中，MAIT 细胞表现出活化和衰竭的表型，其特征是 CD25 和程序性细胞死亡 1 (PD1) 高表达以及促炎细胞因子、IL-2、IFN-γ 和 TNF-α 的产生减少. 尽管来自这些患者的 MAIT 细胞显示出上调的 IL-17 和 IL-4 产生，但 MAIT 细胞的多功能性降低（MAIT 细胞的中位数为 4.8% 对 13.14%，p < 0.001）并且 MAIT 细胞的频率不产生任何效应子分析的分子增加（中位数 34.40 对 19.30% 的 MAIT 细胞，p < 0.01)。几个 MAIT 细胞变量与 HbA 1c水平相关，尤其是在新近发病的 1 型糖尿病患者中。在患有长期 1 型糖尿病的女性中，MAIT 细胞改变在患有相关自身免疫性疾病的女性中比在没有其他自身免疫性疾病的女性中更为明显。在患有长期 1 型糖尿病和相关自身免疫性疾病的女性中，CD69 表达增加，B 细胞淋巴瘤 2 (BCL-2) ( p < 0.05) 和 CD127 (IL-7R)的存活率降低( p < 0.01) 标记表达与没有伴随自身免疫性疾病的女性相比。关于效应分子，MAIT 细胞产生的 TNF-α 和颗粒酶 B 减少。
结论/解释
与近期发病的 1 型糖尿病患者相比，长期 1 型糖尿病患者的 MAIT 细胞频率、表型和功能的变化更为明显。MAIT 细胞变量与临床特征之间存在多种相关性。此外，患有长期 1 型糖尿病的女性存在另一种自身免疫性疾病，进一步加剧了 MAIT 细胞的改变。我们的研究结果表明，成人 1 型糖尿病的 MAIT 细胞改变可能与该疾病的两个方面有关：葡萄糖稳态受损；和自身免疫。
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