Fever is a highly conserved response to infection or injury and benefits organism survival and the resolution of many infections. Emerging evidence suggests that fever-range thermal stress (38–40°C) plays an active role in directing migration of immune cells into secondary lymphoid organs or inflammatory sites. 

However, whether and how fever can regulate the function of integrins, the key cell adhesion molecules in mediating immune cell trafficking, has remained obscure.  

In a recent study published in Immunity, Prof. CHEN Jianfeng’s lab at the Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, in collaboration with colleagues, demonstrated that fever promotes T lymphocyte trafficking through heat shock protein 90 (Hsp90)-induced α4 integrin activation and signaling in T cells.  

By using T cells from mice, the scientists found that fever increased Hsp90 expression in T cells and promoted α4 integrin-mediated T cell adhesion and transmigration.   

Hsp90 was found to bind to the α4 tail and activate α4 integrins via inside-out signaling. The N and C termini of one Hsp90 molecule were found to simultaneously bind to two α4 tails, leading to dimerization and clustering of α4 integrins on the cell membrane and subsequent activation of the FAK-RhoA pathway to promote T cell migration.   

In addition, the scientists generated a knock-in mice line to disrupt Hsp90-α4 interaction in vivo and used several fever mouse models to study the biological function of the Hsp90-α4 integrin pathway. 

They found abolishment of Hsp90-α4 interaction significantly inhibited fever-induced T cell trafficking to draining lymph nodes and impaired the clearance of Salmonella typhimurium infection.   

These findings identified the Hsp90-α4 integrin axis as a novel thermal sensory pathway that promotes T cell trafficking and enhances immune surveillance during infection. In addition to T cells, this mechanism can apply to different immune cells expressing α4 integrins like monocytes and B cells, suggesting its general role in both innate and adaptive immune responses.