Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Diabetologia. 2012 Aug;55(8):2238-45. doi: 10.1007/s00125-012-2547-8. Epub 2012 Apr 11.
AIMS/HYPOTHESIS: The aim of this study was to understand the role of CXC chemokine receptor 3 (CXCR3), a T-helper 1(Th1) type chemokine receptor, in the pathogenesis of type 1 diabetes.
We observed the incidence of diabetes in Cxcr3 homozygous knockout mice. We compared the expression pattern of various cytokines and chemokines and the frequency of FOXP3(+) cells in the pancreas and pancreatic lymph nodes from Cxcr3 ( -/- ) NOD mice and wild-type NOD mice. In addition, we observed the migration ability of CXCR3(+)CD4(+) cells to pancreatic islets upon adoptive transfer. Finally, we examined whether Cxcr3 (+) regulatory T cells (Tregs) actually suppressed the onset of diabetes in vivo.
Cxcr3 ( -/- ) NOD mice developed spontaneous diabetes earlier than did wild-type NOD mice. In Cxcr3 ( -/- ) NOD mice, Tregs were more frequent in pancreatic lymph nodes and less frequent in pancreatic islets than in wild-type NOD mice. While transferred CXCR3(-)CD4(+) cells from wild-type NOD mice did not infiltrate pancreatic islets of NOD-severe combined immunodeficiency (SCID) mice, CXCR3(+)CD4(+) cells from the same mice migrated into the recipient islets and contained Forkhead box P3 (FOXP3) upon adoptive transfer. Moreover, CD4(+)CD25(+) cells from wild-type NOD mice suppressed and delayed the onset of diabetes compared with those from Cxcr3 ( -/- ) NOD mice in a cyclophosphamide-induced diabetes model system.
CONCLUSIONS/INTERPRETATION: The mechanism of accelerated diabetes onset in Cxcr3 ( -/- ) NOD mice was considered to be due to the lack of hybrid Tregs (CXCR3(+)FOXP3(+)CD4(+) cells), which could effectively migrate into and regulate Th1 inflammation in local lesions under Cxcr3 knockout conditions.
目的/假设：本研究旨在了解 CXC 趋化因子受体 3（CXCR3），一种 Th1 型趋化因子受体，在 1 型糖尿病发病机制中的作用。
我们观察了 Cxcr3 纯合敲除小鼠的糖尿病发病率。我们比较了 Cxcr3（-/-）NOD 小鼠和野生型 NOD 小鼠胰腺和胰腺淋巴结中各种细胞因子和趋化因子的表达模式以及 FOXP3（+）细胞的频率。此外，我们观察了 CXCR3（+）CD4（+）细胞在过继转移后向胰岛的迁移能力。最后，我们检查了 Cxcr3（+）调节性 T 细胞（Treg）是否实际上在体内抑制了糖尿病的发作。
Cxcr3（-/-）NOD 小鼠比野生型 NOD 小鼠更早自发发生糖尿病。在 Cxcr3（-/-）NOD 小鼠中，Tregs 在胰腺淋巴结中更为频繁，而在胰腺胰岛中则比野生型 NOD 小鼠更为罕见。虽然来自野生型 NOD 小鼠的转导 CXCR3（-）CD4（+）细胞不会浸润 NOD-严重联合免疫缺陷（SCID）小鼠的胰岛，但来自同一小鼠的 CXCR3（+）CD4（+）细胞在过继转移后迁移到受者胰岛中并含有叉头框 P3（FOXP3）。此外，与 Cxcr3（-/-）NOD 小鼠相比，来自野生型 NOD 小鼠的 CD4（+）CD25（+）细胞在环磷酰胺诱导的糖尿病模型系统中抑制和延迟了糖尿病的发作。
结论/解释：Cxcr3（-/-）NOD 小鼠糖尿病发病加速的机制被认为是由于缺乏混合 Tregs（CXCR3（+）FOXP3（+）CD4（+）细胞），在 Cxcr3 敲除条件下，这些细胞可以有效地迁移到局部病变中并调节 Th1 炎症。
