Ambient temperature regulates CD4⁺ T cell tonic T cell receptor signaling and responsiveness

Mice (Mus musculus) used in biomedical research are commonly housed at 19-23 °C, below their thermoneutral zone (29-34 °C), where metabolic homeostasis occurs. Although traditional housing exposes mice to chronic cold stress and modulates their immune response, cellular mechanisms by which thermoneutrality shapes immune responses remain underdefined. CD4+ T cells are major contributors to host immunity through T cell receptor (TCR) signaling activated via recognition of peptide-major histocompatibility complex class II (pMHCII). We demonstrate that thermoneutral housing, compared to traditional housing, enhances tonic TCR signaling, upregulates genes associated with endogenous TCR stimulation, and increases TCR-driven TNF expression in CD4⁺ T cells. Mechanistically, these effects are in part dependent on tonic TCR engagement with self-pMHCII. In inflammatory disease models, thermoneutrality-driven increased CD4⁺ T cell TNF production correlates with amplified tissue inflammation. Together, these findings reveal how housing temperature may shape inflammatory responses through self-pMHCII-dependent TCR signaling in CD4⁺ T cells.