Regulation of T helper cell responses during antigen presentation by norepinephrine‐exposed endothelial cells

SummaryDermal blood vessels and regional lymph nodes are innervated by sympathetic nerves and, under stress, sympathetic nerves release norepinephrine (NE). Exposure of primary murine dermal microvascular endothelial cells (pDMECs) toNEfollowed by co‐culture with Langerhans cells (LCs), responsiveCD4+T‐cells and antigen resulted in modulation ofCD4+T‐cell responses.NE‐treatment ofpDMECs induced increased production of interleukin (IL)‐6 andIL‐17A while down‐regulating interferon (IFN)‐γandIL‐22 release. This effect did not require contact betweenpDMECs andLCs or T‐cells and depended uponpDMECproduction ofIL‐6. The presence ofNE‐treatedpDMECs increased the proportion ofCD4+T‐cells expressing intracellularIL‐17A and increasedIL‐17AmRNAwhile decreasing the proportion ofIFN‐γ‐ orIL‐22‐expressingCD4+T‐cells andmRNAlevels for those cytokines. Retinoic acid receptor‐related orphan receptor gamma (ROR‐γt)mRNAwas significantly increased inCD4+T‐cells while T‐box transcription factor (T‐bet)mRNAwas decreased. Intradermal administration ofNEprior to hapten immunization at the injection site produced a similar bias in draining lymph nodeCD4+T‐cells towardsIL‐17A and away fromIFN‐γandIL‐22 production. Under stress, release ofNEmay have significant regulatory effects on the outcome of antigen presentation through actions onECs with enhancement of inflammatory skin disorders involving IL‐17/T helper type 17 (Th17) cells.