Fever Promotes T Cell Trafficking Via Heat Shock Proteins

In a recent study published in Immunity, JianFeng Chen from 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.

Fever is a highly conserved response to infection and injury, and it 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 the 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 the present study, the scientists found that fever increased Hsp90 expression in mouse T cells and promoted α4 integrin–mediated T cell adhesion and transmigration.

According to the study, Hsp90 binds to the α4 tail and activates α4 integrins via inside-out signaling. The N and C termini of one Hsp90 molecule 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.

The scientists also generated a knock-in mouse 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. In this study, they found that abolishment of Hsp90-α4 interaction significantly inhibited fever-induced trafficking of T cells to draining lymph nodes and thus 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 other immune cells expressing α4 integrins like monocytes and B cells, suggesting its general role in both innate and adaptive immune responses.