Fever and the thermal regulation of immunity: the immune system feels the heat

Fever is a cardinal response to infection that has been conserved in warm and cold-blooded vertebrates for over 600 million years of evolution. The fever response is executed by integrated physiological and neuronal circuitry and confers a survival benefit during infection. Here, we review our current understanding of how the inflammatory cues delivered by the thermal element of fever stimulate innate and adaptive immune responses. We further highlight the unexpected multiplicity of roles of the pyrogenic cytokine interleukin-6 (IL-6), both during fever induction as well as during the mobilization of lymphocytes to the lymphoid organs that are the staging ground for immune defence. Finally, we discuss the emerging evidence that suggests the adrenergic signalling pathways associated with thermogenesis shape immune cell function.