Differences in body temperature drive sex-specific immune responses

Human body temperature is sexually dimorphic, with females averaging 0.1-0.5°C warmer than males. Body temperature is also linked to immune responses through highly conserved fever and heat shock pathways. We hypothesized that subtle temperature differences observed between sexes could mediate sex differences in immune responses, with potential clinical implications. To test this, we analyzed 973 healthy adults from the Milieu Intérieur cohort, first confirming significant sex and age effects on body temperature within the homeostatic range. Strikingly, within the narrow 36-38°C healthy range, we observed significant, sex-specific associations with both baseline and induced immune responses upon stimulation. In males, higher temperature was associated with decreased type I IFN pathway responses following bacterial and viral ligand stimulation, whereas in females, it correlated with decreased type II IFN responses after superantigen stimulation. Using precise ex vivo stimulation at fever temperatures and single-cell readouts, we confirmed that temperature-immune associations persist beyond homeostatic levels, highlighting their relevance in pathological conditions. This study provides new insights into how natural variation in body temperature across individuals and throughout life may contribute to the immune variation underlying sex disparities in disease.