Karumuthil-Melethil Subha, Perez Nicolas, Li Ruobing, Vasu Chenthamarakshan
Department of Surgery, College of Medicine, University of Illinois, Chicago, IL 60612, USA.
J Immunol. 2008 Dec 15;181(12):8323-34. doi: 10.4049/jimmunol.181.12.8323.
Studies have suggested a correlation between the decline in infectious diseases and increase in the incidence of type 1 diabetes (T1D) in developed countries. Pathogens influence the disease outcome through innate immune receptors such as TLRs. Here we report the effect of ligation of TLR2 and dectin 1 on APCs and the influence of innate immune response induced through these receptors on T1D. Exposure of APCs of NOD mice to zymosan, a fungal cell wall component that interacts with TLR2 and dectin 1, resulted in the release of significant amounts of IL-10, TGF-beta1, IL-2, and TNF-alpha. Treatment of pre- and early hyperglycemic mice with zymosan resulted in suppression of insulitis, leading to a significant delay in hyperglycemia. T cells from zymosan-treated mice showed reduced ability to induce diabetes in NOD-Scid mice compared with control T cells. Zymosan treatment induced suppression of T1D was associated with an increase in the L-selectin(high) T cell frequencies and enhanced suppressor function of CD4(+)CD25(+) T regulatory cells. Further, activation by anti-CD3-Ab induced larger amounts of TGF-beta1 and/or IL-10 production by CD4(+)CD25(+) and CD4(+)CD25(-) T cells from zymosan-treated mice. These results show that innate immune response through TLR2 and dectin 1 results in suppressor cytokine production by APCs and promotes the regulatory function of T cells. Our study demonstrates the possible involvement of signaling through innate immune receptors such as TLR2 and dectin 1 in reduced T1D incidence under the conditions of low hygiene, and the potential of targeting them for treating T1D.
研究表明，在发达国家，传染病发病率的下降与1型糖尿病（T1D）发病率的上升之间存在关联。病原体通过Toll样受体（TLR）等天然免疫受体影响疾病的发生发展。在此，我们报告了TLR2和dectin 1的激活对抗原呈递细胞（APC）的影响，以及通过这些受体诱导的天然免疫反应对T1D的影响。将NOD小鼠的APC暴露于酵母聚糖（一种与TLR2和dectin 1相互作用的真菌细胞壁成分），会导致大量白细胞介素-10（IL-10）、转化生长因子-β1（TGF-β1）、白细胞介素-2（IL-2）和肿瘤坏死因子-α（TNF-α）的释放。用酵母聚糖治疗血糖升高前期和早期的小鼠，可抑制胰岛炎，从而显著延缓高血糖的发生。与对照T细胞相比，来自酵母聚糖治疗小鼠的T细胞在NOD-Scid小鼠中诱导糖尿病的能力降低。酵母聚糖治疗诱导的T1D抑制与L-选择素高表达T细胞频率的增加以及CD4(+)CD25(+)调节性T细胞抑制功能的增强有关。此外，抗CD3抗体激活后，来自酵母聚糖治疗小鼠的CD4(+)CD25(+)和CD4(+)CD25(-) T细胞产生的TGF-β1和/或IL-10量更多。这些结果表明，通过TLR2和dectin 1的天然免疫反应可导致APC产生抑制性细胞因子，并促进T细胞的调节功能。我们的研究证明，在低卫生条件下，通过TLR2和dectin 1等天然免疫受体的信号传导可能与T1D发病率降低有关，并且针对这些受体治疗T1D具有潜力。
