Hultcrantz M, Jacobson S, Hill N J, Santamaria P, Flodström-Tullberg M
Center for Infectious Medicine, Department of Medicine HS, Karolinska Institutet, Karolinska University Hospital Huddinge, F59, 141 86 Stockholm, Sweden.
Diabetologia. 2009 Feb;52(2):299-305. doi: 10.1007/s00125-008-1193-7. Epub 2008 Nov 25.
AIMS/HYPOTHESIS: The pancreatic beta cell response to cytokines is crucial for the development of type 1 diabetes in the NOD mouse. For example, beta cell production of suppressor of cytokine signalling-1 (SOCS-1) protects against diabetes. This finding and other recent studies indicated that cytokine-stressed beta cells might contribute to disease progression by affecting the pancreatic lymphocyte infiltrate. The aim of this study was to provide insight into how the beta cell influences the pancreas-infiltrating T cell repertoire.
Lymphocytes isolated from Socs1-transgenic (tg) and non-tg NOD mice were analysed by flow cytometry. mRNA and protein levels in pancreatic islets were measured by real-time PCR and immunofluorescence analysis, respectively.
The percentages of regulatory T cells, total counts and ratios between infiltrating CD8+ and CD4+ T cells, and the expression of killer cell lectin-like receptor subfamily K, member 1 (NKG2D) on CD8+ T cells did not differ in pancreases from prediabetic Socs1-tg and non-tg NOD mice. However, a striking difference in the percentages of CD8+ T cells specific for glucose 6-phosphatase catalytic subunit-related protein 206-214 was found, showing that SOCS-1 prevents the accumulation of high percentages of self-reactive CD8+ T cells in the pancreas. It was also found that protection from diabetes in Socs1-tg NOD mice correlated with a reduced expression of Cxcl10 mRNA in IFN-gamma treated islets.
CONCLUSIONS/INTERPRETATION: This study highlights an important role for the beta cell in the local regulation of the diabetogenic process. By responding to the pro-inflammatory pancreas milieu it strongly influences the islet-reactive T cell repertoire in the pancreas.
目的/假设：胰岛β细胞对细胞因子的反应对于非肥胖糖尿病（NOD）小鼠1型糖尿病的发展至关重要。例如，β细胞产生的细胞因子信号转导抑制因子1（SOCS-1）可预防糖尿病。这一发现以及其他近期研究表明，受到细胞因子应激的β细胞可能通过影响胰腺淋巴细胞浸润而促进疾病进展。本研究的目的是深入了解β细胞如何影响胰腺浸润性T细胞库。
通过流式细胞术分析从Socs1转基因（tg）和非tg NOD小鼠分离的淋巴细胞。分别通过实时PCR和免疫荧光分析测量胰岛中的mRNA和蛋白质水平。
在糖尿病前期Socs1-tg和非tg NOD小鼠的胰腺中，调节性T细胞的百分比、浸润的CD8 +和CD4 + T细胞的总数及比例，以及CD8 + T细胞上杀伤细胞凝集素样受体亚家族K成员1（NKG2D）的表达没有差异。然而，发现针对葡萄糖6-磷酸酶催化亚基相关蛋白206-214的CD8 + T细胞百分比存在显著差异显示，SOCS-1可防止胰腺中高百分比的自身反应性CD8 + T细胞积累。还发现Socs1-tg NOD小鼠对糖尿病的保护作用与IFN-γ处理的胰岛中Cxcl10 mRNA表达降低相关。
结论/解读：本研究强调了β细胞在糖尿病发生过程局部调节中的重要作用。通过对促炎性胰腺微环境作出反应，它强烈影响胰腺中胰岛反应性T细胞库。
