TLR4 hyperresponsiveness via cell surface expression of heat shock protein gp96 potentiates suppressive function of regulatory T cells
TLR4 hyperresponsiveness via cell surface expression of heat shock protein gp96 potentiates suppressive function of regulatory T cells
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DOI：
10.4049/jimmunol.178.5.3219
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发表时间：
2007-03-01
影响因子：
4.4
通讯作者：
Li, Zihai
中科院分区：
文献类型：
--
作者：
Dai, Jie;Liu, Bei;Li, Zihai
热休克蛋白gp 96作为内质网未折叠蛋白反应的主要介质之一，也是包括TLR 4在内的多种TLR的专性伴侣。我们最近证明，在转基因（Tg）小鼠（96 tm-Tg）中，gp 96的细胞表面表达增强，赋予对LPS的高反应性，并诱导TLR 4依赖性狼疮样自身免疫性疾病。在本研究中，我们研究了CD 4（+）CD 25（+）Foxp 3（+）调节性T细胞（T-reg）在这些小鼠中的功能，鉴于T-reg在维持对自身抗原的外周耐受中的重要作用以及TLR信号对T-reg调节的日益增强的赞赏。与T-reg活性减弱的预测相反，我们发现在96 tm-Tg小鼠中T-reg的抑制功能增强。在新生儿期T-reg的失活不仅加剧了器官特异性疾病，而且还加剧了全身性自身免疫性疾病。通过将96 tm-Tg小鼠与TLR 4空白背景杂交，我们证明了TLR 4在T-reg抑制功能放大中的关键作用。这些发现说明gp 96通过增强促炎反应和诱导T-reg功能在调节免疫反应中起双重作用，这两者都依赖于其陪伴TLR 4的能力。我们的研究为TLR连接抑制炎症和自身免疫性疾病提供了强有力的支持。
As one of the main mediators of the endoplasmic reticulum unfolded protein response, heat shock protein gp96 is also an obligate chaperone for multiple TLRs including TLR4. We demonstrated recently that enforced cell surface expression of gp96 in a transgenic (Tg) mouse (96tm-Tg) conferred hyperresponsiveness to LPS and induced TLR4-dependent lupus-like autoimmune diseases. In this study, we investigated the function of CD4(+)CD25(+) Foxp3(+) regulatory T cells (T-reg) in these mice in light of the important roles of T-reg in the maintenance of peripheral tolerance against self-Ag as well as the increasing appreciation of TLR signaling on the regulation of T-reg. We found that the development of T-reg was not impaired in 96tm-Tg mice. Contrary to the prediction of dampened T-reg activity, we discovered that the suppressive functions of T-reg were increased in 96tm-Tg mice. Inactivation of T-reg during the neonatal stage of life exacerbated not only organ-specific diseases but also systemic autoimmune diseases. By crossing 96tm-Tg mice into the TLR4 null background, we demonstrated the critical roles of TLR4 in the amplification of T-reg suppressive function. These findings illustrate that gp96 plays dual roles in regulating immune responses by augmenting proinflammatory responses and inducing T-reg function, both of which are dependent on its ability to chaperone TLR4. Our study provides strong support to the notion of compensatory T-reg activation by TLR ligation to dampen inflammation and autoimmune diseases.