Activation of dendritic cells via TLR7 reduces Foxp3 expression and suppressive function in induced Tregs
Activation of dendritic cells via TLR7 reduces Foxp3 expression and suppressive function in induced Tregs
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DOI：
10.1002/eji.201041014
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发表时间：
2011-05-01
影响因子：
5.4
通讯作者：
Krug, Anne B.
中科院分区：
文献类型：
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作者：
Hackl, Daniela;Loschko, Jakob;Krug, Anne B.
Toll样受体（TLR）7的外源性和内源性RNA配体在病毒感染或自身免疫性疾病如系统性红斑狼疮（SLE）期间存在，其直接激活DC和B细胞，从而支持效应T和B淋巴细胞的产生。然而，有效的抗病毒或自身反应性适应性免疫应答的产生需要通过TdR阻断免疫抑制。在这项研究中，我们表明，TLR 7配体在体外和体内减少从幼稚小鼠T细胞从头产生的Tcl 3的数量。在TLR 7激活的脾DC存在下，Foxp 3在幼稚T细胞中被TGF-β瞬时诱导，但在随后的时间点下调。中和实验表明，初始诱导后Foxp 3的丢失主要取决于含有TLR 7配体的DC-T细胞共培养物中产生的IL-6。因此，在TLR 7配体的影响下，产生更少的TcR，并且这些TcR表达更低水平的Foxp 3，这与抑制应答T细胞增殖的能力降低相关。因此，我们提供的证据表明，TLR 7配体影响Treg依赖性免疫调节，从而可能有助于自身免疫性疾病，如系统性红斑狼疮的发展。
Exogenous and endogenous RNA ligands of Toll-like receptor (TLR) 7 which are present during viral infection or autoimmune diseases such as systemic lupus erythematosus (SLE) directly activate DCs and B cells and thus support the generation of effector T and B lymphocytes. However, the generation of effective antiviral or autoreactive adaptive immune responses requires blocking of immunosuppression by Tregs. In this study, we show that TLR7 ligands reduce the number of Tregs generated de novo from naive murine T cells in vitro and in vivo. In the presence of TLR7-activated splenic DCs, Foxp3 was transiently induced in naive T cells by TGF-beta but was downregulated at later time points. Neutralization experiments revealed that loss of Foxp3 after initial induction was mostly dependent on IL-6 produced in the DC-T-cell cocultures containing TLR7 ligands. Thus, under the influence of TLR7 ligands fewer Tregs were generated and these expressed lower levels of Foxp3 correlating with a reduced capacity to suppress responder T-cell proliferation. Thus, we provide evidence that TLR7 ligands affect Treg-dependent immune regulation and may thereby contribute to the development of autoimmune diseases such as systemic lupus erythematosus.