Department of Endocrinology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
Department of Pediatrics, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
Pediatr Diabetes. 2019 May;20(3):271-281. doi: 10.1111/pedi.12813. Epub 2019 Jan 27.
Regulatory T cells (Tregs) play an important role in maintaining tolerance to self-antigens. Defects in the frequency and function of polyclonal Tregs have been reported in type 1 diabetes (T1D). However, characteristics of proinsulin (PI)-specific Tregs in human T1D have not yet been explored. Therefore, we aimed to characterize PI-specific Tregs in two distinct pathophysiological subtypes of T1D, juvenile-onset T1D (JOT1D) and adult-onset T1D (AOT1D), distinguished by the age of onset.
Peripheral blood mononuclear cells of the recruited subjects were stimulated in vitro with PI-derived peptides. PI-specific Tregs were characterized by flow cytometry using the combination of markers CD25, CD137, FOXP3 and CD45RA.
Firstly, we observed similar frequencies of polyclonal Tregs in the T1D (n = 25) and healthy control (HC) (n = 20) subjects (P = 0.96), with a positive correlation between age and frequency of polyclonal Tregs (r = +0.35, P = 0.04). While the frequency of polyclonal Tregs was higher in AOT1D group (P = 0.02), both JOT1D (n = 14) and AOT1D groups (n = 11) had a comparable frequency of PI-specific Tregs in their peripheral blood. The frequency of PI-specific memory Tregs was significantly high in both the JOT1D (P = 0.02) and AOT1D (P = 0.009) groups compared to their respective HC groups (n = 10). Finally, we observed no significant difference in the expression of FOXP3 and IL-2 receptor in PI-specific Tregs in all the groups.
Unlike polyclonal Tregs, both T1D subtypes harbor comparable frequencies of PI-specific Tregs. Chronic antigen presentation results in a distinct memory-like phenotype of PI-specific Tregs in these subjects irrespective of the age of disease onset.
调节性 T 细胞（Tregs）在维持对自身抗原的耐受方面发挥着重要作用。1 型糖尿病（T1D）患者中已报道多克隆 Tregs 的频率和功能存在缺陷。然而，人类 T1D 中胰岛素原（PI）特异性 Tregs 的特征尚未得到探索。因此，我们旨在描述两种不同病理生理亚型 T1D（分别为青少年起病的 T1D（JOT1D）和成年起病的 T1D（AOT1D））中 PI 特异性 Tregs 的特征，其区分标准为发病年龄。
招募的受试者外周血单个核细胞在体外用 PI 衍生肽刺激。通过流式细胞术，使用 CD25、CD137、FOXP3 和 CD45RA 标志物的组合来鉴定 PI 特异性 Tregs。
首先，我们观察到 T1D（n=25）和健康对照（HC）（n=20）受试者的多克隆 Tregs 频率相似（P=0.96），且多克隆 Tregs 频率与年龄呈正相关（r=+0.35，P=0.04）。AOT1D 组多克隆 Tregs 频率更高（P=0.02），而 JOT1D（n=14）和 AOT1D 组（n=11）在其外周血中具有可比的 PI 特异性 Tregs 频率。与各自的 HC 组（n=10）相比，JOT1D（P=0.02）和 AOT1D（P=0.009）组的 PI 特异性记忆 Tregs 频率均显著升高。最后，我们观察到所有组中 PI 特异性 Tregs 中 FOXP3 和 IL-2 受体的表达均无显著差异。
与多克隆 Tregs 不同，两种 T1D 亚型均具有可比的 PI 特异性 Tregs 频率。慢性抗原呈递导致这些受试者中 PI 特异性 Tregs 呈现独特的记忆样表型，而与疾病发病年龄无关。
