Fever Promotes T Lymphocyte Trafficking Via A Thermal Sensory Pathway Involving Heat Shock Protein 90 And Alpha 4 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.