AbstractThe induction of heat shock proteins by heat shock is classically defined as the heat shock response, which is involved in cytoprotection, inflammation and immune responses. Whereas the cytoprotective properties of heat shock have been well characterized, the immunomodulating roles of the heat shock response on the immune system are just emerging. In particular, it is not known whether immunomodulating functions of heat are mediated by the heat shock response. We addressed this question genetically, using a murine model that is unable to mount the heat shock response because of deletion of a major transcriptional factor, heat shock factor 1 (Hsf1). We focused on the roles of heat shock on modulating the functions of dendritic cells (DC) because of their important roles in both innate and adaptive immunity. We found that heat shock matures CD11c+ DC both in vitro and in vivo, phenotypically and functionally, in the absence of any exogenous inflammatory stimuli. Furthermore, heat‐shock‐mediated DC maturation is independent of Hsf1, as Hsf1–/– DC can be matured by heat shock equally well as wild‐type DC. Our novel findings demonstrate that heat shock, one of the most primitive biological responses, can modulate the immune response without the requirement for the transcriptional induction/repression of target genes mediated by Hsf1.