Center for Infectious Diseases and Microbiology Translational Research, Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, McGuire Translational Research Facility, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Eur J Immunol. 2011 Jan;41(1):29-38. doi: 10.1002/eji.201040717. Epub 2010 Dec 3.
Innate immune activation via TLR induces dendritic cell maturation and secretion of inflammatory mediators, generating favorable conditions for naïve T-cell activation. Here, we demonstrate a previously unknown function for TLR5, namely that it enhances MHC class-II presentation of flagellin epitopes to CD4(+) T cells and is required for induction of robust flagellin-specific adaptive immune responses. Flagellin-specific CD4(+) T cells expanded poorly in TLR5-deficient mice immunized with flagellin, a deficiency that persisted even when additional TLR agonists were provided. Flagellin-specific IgG responses were similarly depressed in the absence of TLR5. In marked contrast, TLR5-deficient mice developed robust flagellin-specific T-cell responses when immunized with processed flagellin peptide. Surprisingly, the adaptor molecule Myd88 was not required for robust CD4(+) T-cell responses to flagellin, indicating that TLR5 enhances flagellin-specific CD4(+) T-cell responses in the absence of conventional TLR signaling. A requirement for TLR5 in generating flagellin-specific CD4(+) T-cell activation was also observed when using an in vitro dendritic cell culture system. Together, these data uncover an Myd88-independent function for dendritic cell TLR5 in enhancing the presentation of peptides to flagellin-specific CD4(+) T cells.
天然免疫激活通过 TLR 诱导树突状细胞成熟并分泌炎症介质，为初始 T 细胞的激活创造有利条件。在这里，我们证明了 TLR5 的一个以前未知的功能，即它增强了鞭毛蛋白表位对 CD4+T 细胞的 MHC Ⅱ类呈递，并且是诱导强烈的鞭毛蛋白特异性适应性免疫反应所必需的。在 TLR5 缺陷型小鼠中用鞭毛蛋白免疫时，鞭毛蛋白特异性 CD4+T 细胞扩增不良，即使提供了额外的 TLR 激动剂，这种缺陷仍然存在。在没有 TLR5 的情况下，鞭毛蛋白特异性 IgG 反应也同样受到抑制。相比之下，当用加工的鞭毛蛋白肽免疫时，TLR5 缺陷型小鼠会产生强烈的鞭毛蛋白特异性 T 细胞反应。令人惊讶的是，衔接分子 Myd88 对于对鞭毛蛋白的强烈 CD4+T 细胞反应不是必需的，这表明 TLR5 在缺乏常规 TLR 信号的情况下增强了鞭毛蛋白特异性 CD4+T 细胞反应。在使用体外树突状细胞培养系统时，也观察到 TLR5 在产生鞭毛蛋白特异性 CD4+T 细胞激活中的作用不依赖于 TLR5。总之，这些数据揭示了树突状细胞 TLR5 在增强对鞭毛蛋白特异性 CD4+T 细胞的肽呈递中的 Myd88 非依赖性功能。
