Du Yanqin, Zhao Mengxiao, Zeng Xiaoqing, Wang Shichuan, Wang Qin, Chen Liwei, Yang Xuecheng, Feng Xuemei, Lu Mengji, Dittmer Ulf, Sutter Kathrin, Zheng Xin, Yang Dongliang, Xu Chunli, Liu Jia
Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, 430022, China.
Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Med Microbiol Immunol. 2025 May 14;214(1):24. doi: 10.1007/s00430-025-00834-2.
Toll-like receptor (TLR) 9 ligand has been reported to induce the formation of intrahepatic myeloid-cell aggregates for T cell population expansion (iMATEs), which enhances responses of cytotoxic T lymphocytes (CTLs). However, little is known about how the formation of iMATEs is regulated. Previously, various studies have demonstrated that regulatory T cells (Tregs) can suppress CTL responses through soluble cytokines or co-inhibitory molecules. It's unclear whether and how Tregs regulate the formation of iMATEs. In this study, we investigated whether Tregs are involved in regulating TLR9-induced iMATEs formation and the mechanisms behind it by using different gene knockout mice and blocking antibodies. We observed that intravenous injection of TLR9 ligand CpG induced significant iMATEs formation, accompanied by a marked increase in the number of Tregs infiltrating the liver as well as upregulation of IL-10 in both peripheral blood and liver. Importantly, depletion of Tregs either by anti-CD4, anti-CD25 blocking antibodies or diphtheria toxin (DT) in DEREG transgenic mice resulted in enhanced CpG-induced iMATEs formation. Conversely, knocking out IL-10 led to increased intrahepatic Treg infiltration and decreased CpG ODN-induced iMATEs formation. Consistently, depleting Kupffer cells (KCs), one of the main source of IL-10, also resulted in reduced formation of iMATEs. In conclusion, our results suggest that IL-10 suppresses Treg infiltration in the liver and thus promote CpG ODN-induced iMATEs formation. These results fill the gap in our understanding of the intrahepatic regulation mechanism of iMATEs formation.
据报道，Toll样受体（TLR）9配体可诱导肝内髓样细胞聚集体的形成，以促进T细胞群体扩增（iMATEs），从而增强细胞毒性T淋巴细胞（CTL）的反应。然而，关于iMATEs的形成是如何被调控的，我们知之甚少。此前，各种研究表明，调节性T细胞（Tregs）可通过可溶性细胞因子或共抑制分子抑制CTL反应。目前尚不清楚Tregs是否以及如何调节iMATEs的形成。在本研究中，我们通过使用不同的基因敲除小鼠和阻断抗体，研究了Tregs是否参与调节TLR9诱导的iMATEs形成及其背后的机制。我们观察到，静脉注射TLR9配体CpG可诱导显著的iMATEs形成，同时肝脏中浸润的Tregs数量显著增加，外周血和肝脏中的IL-10也上调。重要的是，在DEREG转基因小鼠中，通过抗CD4、抗CD25阻断抗体或白喉毒素（DT）清除Tregs，导致CpG诱导的iMATEs形成增强。相反，敲除IL-10导致肝内Treg浸润增加，CpG ODN诱导的iMATEs形成减少。同样，清除IL-10的主要来源之一库普弗细胞（KCs），也导致iMATEs形成减少。总之，我们的结果表明，IL-10抑制Tregs在肝脏中的浸润，从而促进CpG ODN诱导的iMATEs形成。这些结果填补了我们对iMATEs形成的肝内调节机制理解上的空白。
