T-BET+CXCR3+调节性T细胞在预防自身免疫性糖尿病中的独特作用。
Singular role for T-BET+CXCR3+ regulatory T cells in protection from autoimmune diabetes.
作者信息
Tan Tze Guan, Mathis Diane, Benoist Christophe
机构信息
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115
出版信息
Proc Natl Acad Sci U S A. 2016 Dec 6;113(49):14103-14108. doi: 10.1073/pnas.1616710113. Epub 2016 Nov 21.
Foxp3 regulatory T (Treg) cells are crucial for restraining inflammation in a variety of autoimmune diseases, including type 1 diabetes (T1D). However, the transcriptional and functional phenotypes of Treg cells within the pancreatic lesion remain poorly understood. Here we characterized pancreas-infiltrating Treg cells in the NOD mouse model of T1D and uncovered a substantial enrichment of the Treg subpopulation expressing the chemokine receptor CXCR3. Accumulation of CXCR3 Treg cells within pancreatic islets was dependent on the transcription factor T-BET, and genetic ablation of T-BET increased the onset and penetrance of disease, abrogating the sex bias normally seen in the NOD model. Both male and female mice lacking T-BET Treg cells showed a more aggressive insulitic infiltrate, reflected most prominently by elevated production of type 1 cytokines. Our results suggest the possibility of fine therapeutic targeting of Treg cells, in a tissue- and cell-subset-specific fashion, as a more focused immunotherapy for T1D.
叉头框蛋白3调节性T（Treg）细胞对于抑制包括1型糖尿病（T1D）在内的多种自身免疫性疾病中的炎症至关重要。然而，胰腺病变内Treg细胞的转录和功能表型仍知之甚少。在此，我们对T1D的非肥胖糖尿病（NOD）小鼠模型中浸润胰腺的Treg细胞进行了表征，并发现表达趋化因子受体CXCR3的Treg亚群大量富集。胰腺胰岛内CXCR3 Treg细胞的积累依赖于转录因子T-盒蛋白（T-BET），T-BET的基因敲除增加了疾病的发病和发病率，消除了NOD模型中通常可见的性别偏差。缺乏T-BET Treg细胞的雄性和雌性小鼠均表现出更具侵袭性的胰岛炎浸润，最显著的表现为1型细胞因子产生增加。我们的结果表明，以组织和细胞亚群特异性方式对Treg细胞进行精准治疗靶向，作为一种更有针对性的T1D免疫疗法具有可能性。
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