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. 2018 Feb;19(1):68-79. doi: 10.1111/pedi.12536. Epub 2017 May 10.
AIMS/HYPOTHESIS: Among the beta-cell associated antigens, preproinsulin (PPI) has been shown to play a key role in the pathogenesis of type 1 diabetes (T1D). PPI-specific autoreactive CD8+ T cells emerge early during beta-cell destruction and persist in peripheral circulation during diabetes progression. However, the influence of insulin therapy on phenotype of autoreactive CD8+ T cells in T1D including, juvenile-onset T1D (JOT1D), and adult-onset T1D (AOT1D) is not yet known.
We followed the time course of PPI-specific CD8+ T cells in JOT1D and AOT1D subjects that achieved glycemic control after 1 year of insulin therapy, using major histocompatibility complex-I (MHC-I) dextramers by flow cytometry.
At follow-up, PPI-specific CD8+ T cells could be detected consistently in peripheral blood of all T1D subjects. Proportion of PPI-specific effector memory (T ) subsets decreased, while central memory T (T ) cells remained unchanged in both groups. Expression of granzyme-B and perforin in PPI-specific CD8+ T cells also remained unchanged. Further, on analysis of B-chain and signal peptide (SP) specific CD8+ T cell responses separately, we again observed decrease in T subset in both the groups, while increase in naive (T ) subset was observed in B-chain specific CD8+ T cells only.
Our study shows that PPI-specific CD8+ T cells can be detected in both JOT1D and AOT1D subjects over a period of time with reliable consistency in frequency but variable pathophysiological characteristics. Insulin therapy seems to reduce the PPI-specific T subsets; however, the PPI-specific T cells continue to persist as attractive targets for immunotherapy.
目的/假设：在胰岛相关抗原中，前胰岛素原（PPI）已被证明在 1 型糖尿病（T1D）的发病机制中起关键作用。在胰岛β细胞破坏过程中，PPI 特异性自身反应性 CD8+T 细胞早期出现，并在糖尿病进展过程中持续存在于外周循环中。然而，胰岛素治疗对 T1D 中自身反应性 CD8+T 细胞表型的影响，包括青少年起病的 T1D（JOT1D）和成年起病的 T1D（AOT1D），目前尚不清楚。
我们使用 MHC-I 二聚体通过流式细胞术，跟踪了 JOT1D 和 AOT1D 患者在接受胰岛素治疗 1 年后血糖控制的时间进程中 PPI 特异性 CD8+T 细胞的变化。
在随访时，所有 T1D 患者的外周血中均能持续检测到 PPI 特异性 CD8+T 细胞。在两组中，PPI 特异性效应记忆（TEM）亚群的比例下降，而中央记忆 T（TCM）细胞保持不变。PPI 特异性 CD8+T 细胞中颗粒酶 B 和穿孔素的表达也保持不变。此外，在分别分析 B 链和信号肽（SP）特异性 CD8+T 细胞反应时，我们再次观察到两组中 TEM 亚群减少，而仅在 B 链特异性 CD8+T 细胞中观察到幼稚（TN）亚群增加。
我们的研究表明，在一段时间内，PPI 特异性 CD8+T 细胞可在 JOT1D 和 AOT1D 患者中检测到，其频率具有可靠的一致性，但具有不同的病理生理特征。胰岛素治疗似乎减少了 PPI 特异性 T 亚群；然而，PPI 特异性 T 细胞仍然是免疫治疗的有吸引力的靶标。
