Stress hormone signalling inhibits Th1 polarization in a CD4 T‐cell‐intrinsic manner via mTORC1 and the circadian gene PER1

Stress hormones are believed to skew the CD4 T‐cell differentiation towards a Th2 response via a T‐cell‐extrinsic mechanism. Using isolated primary human naïve and memory CD4 T cells, here we show that both adrenergic‐ and glucocorticoid‐mediated stress signalling pathways play a CD4 naïve T‐cell‐intrinsic role in regulating the Th1/Th2 differentiation balance. Both stress hormones reduced the Th1 programme and cytokine production by inhibiting mTORC1 signalling via two parallel mechanisms. Stress hormone signalling inhibited mTORC1 in naïve CD4 T cells (1) by affecting the PI3K/AKT pathway and (2) by regulating the expression of the circadian rhythm gene, period circadian regulator 1 (PER1). Both stress hormones induced the expression of PER1, which inhibited mTORC1 signalling, thus reducing Th1 differentiation. This previously unrecognized cell‐autonomous mechanism connects stress hormone signalling with CD4 T‐cell differentiation via mTORC1 and a specific circadian clock gene, namely PER1.