TLR4 signaling via MyD88 and TRIF differentially shape the CD4+ T cell response to Porphyromonas gingivalis hemagglutinin B.
TLR4 signaling via MyD88 and TRIF differentially shape the CD4+ T cell response to Porphyromonas gingivalis hemagglutinin B.
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DOI：
10.4049/jimmunol.1003192
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发表时间：
2011-05-15
期刊：
影响因子：
--
通讯作者：
Katz J
中科院分区：
文献类型：
--
作者：
Gaddis DE;Michalek SM;Katz J
重组血凝素B（rHag B）是牙周致病菌牙龈卟啉单胞菌的一种毒力因子，已被证明可诱导针对细菌感染的保护性免疫。此外，我们已经证明rHagB是树突状细胞的TLR 4激动剂。然而，目前尚不清楚rHagB树突状细胞刺激如何影响T细胞的活化和分化。因此，我们进行了目前的研究，以检查TLR 4信号转导在形成CD 4 + T细胞反应后，小鼠免疫rHagB的作用。用该Ag免疫导致特异性CD 4 + T细胞和Ab应答的诱导。在TLR 4 −/−和MyD 88 −/−但不含Toll/IL-1 R结构域的衔接子诱导IFN-β缺陷型（TRIFLps 2）小鼠中，与野生型小鼠相比，Th 2 CD 4 + T细胞亚群增加，Th 1亚群减少，HagB特异性抗体的血清IgG 1/IgG 2水平较高。这些发现伴随着加塔-3和Foxp 3表达的增加以及从TLR 4 −/−和MyD 88 −/−小鼠分离的CD 4 + T细胞活化的减少。有趣的是，TLR 4 −/− CD 4 + T细胞显示IL-2/STAT 5信号传导增加。而TRIF缺乏对CD 4 + T细胞应答的影响最小，它导致记忆性CD 4 + T细胞产生的IFN-γ和IL-17增加。据我们所知，这些结果首次证明TLR 4信号通过下游MyD 88和TRIF分子对CD 4 + T细胞对HagB Ag的反应产生差异调节。从目前的工作中获得的见解将有助于设计更好的治疗策略，对牙龈卟啉单胞菌感染。
Recombinant hemagglutinin B (rHagB), a virulence factor of the periodontal pathogen Porphyromonas gingivalis, has been shown to induce protective immunity against bacterial infection. Furthermore, we have demonstrated that rHagB is a TLR4 agonist for dendritic cells. However, it is not known how rHagB dendritic cell stimulation affects the activation and differentiation of T cells. Therefore, we undertook the present study to examine the role of TLR4 signaling in shaping the CD4+ T cell response following immunization of mice with rHagB. Immunization with this Ag resulted in the induction of specific CD4+ T cells and Ab responses. In TLR4−/− and MyD88−/− but not Toll/IL-1R domain-containing adapter inducing IFN-β–deficient (TRIFLps2) mice, there was an increase in the Th2 CD4+ T cell subset, a decrease in the Th1 subset, and higher serum IgG1/IgG2 levels of HagB-specific Abs compared with those in wild-type mice. These finding were accompanied by increased GATA-3 and Foxp3 expression and a decrease in the activation of CD4+ T cells isolated from TLR4−/− and MyD88−/− mice. Interestingly, TLR4−/− CD4+ T cells showed an increase in IL-2/STAT5 signaling. Whereas TRIF deficiency had minimal effects on the CD4+ T cell response, it resulted in increased IFN-γ and IL-17 production by memory CD4+ T cells. To our knowledge, these results demonstrate for the first time that TLR4 signaling, via the downstream MyD88 and TRIF molecules, exerts a differential regulation on the CD4+ T cell response to HagB Ag. The gained insight from the present work will aid in designing better therapeutic strategies against P. gingivalis infection.
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