Fever Promotes T Lymphocyte Trafficking via a Thermal Sensory Pathway Involving Heat Shock Protein 90 and α4 Integrins

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 alpha 4 integrin activation and signaling in T cells. By inducing selective binding of Hsp90 to alpha 4 integrins, but not beta 2 integrins, fever increased alpha 4-integrin-mediated T cell adhesion and transmigration. Mechanistically, Hsp90 bound to the alpha 4 tail and activated alpha 4 integrins via inside-out signaling. Moreover, the N and C termini of one Hsp90 molecule simultaneously bound to two alpha 4 tails, leading to dimerization and clustering of alpha 4 integrins on the cell membrane and subsequent activation of the FAK-RhoA pathway. Abolishment of Hsp90-alpha 4 interaction inhibited fever-induced T cell trafficking to draining lymph nodes and impaired the clearance of bacterial infection. Our findings identify the Hsp90-alpha 4-]integrin axis as a thermal sensory pathway that promotes T lymphocyte trafficking and enhances immune surveillance during infection.