Cutting edge: Vasoactive intestinal peptide (VIP) induces differentiation of Th17 cells with a distinctive cytokine profile

Immune cellular effects of vasoactive intestinal peptide (VIP) are transduced by VIP G protein-coupled receptors type 1 (VPAC(1)) and type 2 (VPAC(2)). We now show that VIP with TGF beta stimulates the transformation of CD4 T cells to a distinctive type of Th17 cell that generates IL-17 but not IL-6 or IL- 21. VIP induction of Th17 cells was higher in VPAC(2) knockout mice than wild-type mice, suggesting that VPAC(2) is the principal transducer. Compared with Th17 cells elicited by IL-6, those evoked by VIP were similar in the secretion of IL-17 and IL-22 but lacked IL-21 secretion. Suppression of VIP induction of Th17 cells by protein kinase A inhibitors and enhancement by pharmacologically increased cAMP supports a role for this signal. The ability of VIP-VPAC(1) axis signals to evoke development of a novel type of Th17 cells demonstrates the unique specificity of neuroregulatory mechanisms in the immunological environment.