Fever Promotes T Lymphocyte Trafficking via a Thermal Sensory Pathway Involving Heat Shock Protein 90 and &agr;4 Integrins

Abstract

Summary 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 &agr;4 integrin activation and signaling in T cells. By inducing selective binding of Hsp90 to &agr;4 integrins, but not &bgr;2 integrins, fever increased &agr;4‐integrin‐mediated T cell adhesion and transmigration. Mechanistically, Hsp90 bound to the &agr;4 tail and activated &agr;4 integrins via inside‐out signaling. Moreover, the N and C termini of one Hsp90 molecule simultaneously bound to two &agr;4 tails, leading to dimerization and clustering of &agr;4 integrins on the cell membrane and subsequent activation of the FAK‐RhoA pathway. Abolishment of Hsp90‐&agr;4 interaction inhibited fever‐induced T cell trafficking to draining lymph nodes and impaired the clearance of bacterial infection. Our findings identify the Hsp90‐&agr;4‐integrin axis as a thermal sensory pathway that promotes T lymphocyte trafficking and enhances immune surveillance during infection. Graphical Abstract Figure. No Caption available. HighlightsFever promotes &agr;4‐integrin‐mediated T cell adhesion and transmigrationHsp90 binds to &agr;4 tails and activates &agr;4 integrins via inside‐out signalingHsp90 triggers dimerization and clustering of &agr;4 integrins to activate FAK‐RhoADisruption of Hsp90‐&agr;4 interaction impairs fever‐induced T cell trafficking &NA; Fever is an evolutionarily conserved response in both endothermic and ectothermic species and confers survival benefits during infection and injury. Lin et al. identify that the Hsp90‐&agr;4‐integrin axis serves as a thermal sensory pathway that responds to fever to promote T cell trafficking and enhance immune surveillance during infection.