Fever is an evolutionarily conserved response that confers survival benefits during infection. However, the underlying mechanism remains obscure. Here, we report that fever promoted T lymphocyte trafficking through heat shock protein 90 (Hsp90)-induced α4 integrin activation and signaling in T cells. By inducing selective binding of Hsp90 to α4 integrins, but not β2 integrins, fever increased α4-integrin-mediated T cell adhesion and transmigration. Mechanistically, Hsp90 bound to the α4 tail and activated α4 integrins via inside-out signaling. Moreover, the N and C termini of one Hsp90 molecule simultaneously bound to two α4 tails, leading to dimerization and clustering of α4 integrins on the cell membrane and subsequent activation of the FAK-RhoA pathway. Abolishment of Hsp90-α4 interaction inhibited fever-induced T cell trafficking to draining lymph nodes and impaired the clearance of bacterial infection. Our findings identify the Hsp90-α4-integrin axis as a thermal sensory pathway that promotes T lymphocyte trafficking and enhances immune surveillance during infection.

中文翻译：

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发烧通过涉及热休克蛋白90和α4整联蛋白的热感觉途径促进T淋巴细胞运输。

发烧是一种进化上保守的反应，可在感染过程中带来生存益处。但是，基本机制仍然不清楚。在这里，我们报道发烧通过热休克蛋白90（Hsp90）诱导T细胞中的α4整合素激活和信号传导促进T淋巴细胞运输。通过诱导Hsp90与α4整联蛋白而非β2整联蛋白的选择性结合，发烧会增加α4整联蛋白介导的T细胞粘附和转运。从机理上讲，Hsp90结合到α4尾部并通过由内而外的信号传导激活α4整联蛋白。此外，一个Hsp90分子的N和C末端同时与两个α4尾部结合，导致α4整联蛋白在细胞膜上二聚化和聚集，并随后激活FAK-RhoA途径。Hsp90-α4相互作用的取消抑制了发烧引起的T细胞向淋巴结引流的运输，并削弱了细菌感染的清除率。我们的发现将Hsp90-α4-整联蛋白轴确定为一种热感觉途径，可促进T淋巴细胞的运输并增强感染期间的免疫监视。