Vasoactive Intestinal Peptide Induces Cell Cycle Arrest and Regulatory Functions in Human T Cells at Multiple Levels

Abstract

Vasoactive intestinal peptide (VIP) is a potent anti-inflammatory neuropeptide that, by inhibiting Th1-driven responses and inducing the emergence of regulatory T cells (T_reg), has been proven successful in the induction of tolerance in various experimental models of autoimmune disorders. Here, we investigate the molecular mechanisms involved in VIP-induced tolerance. VIP treatment in the presence of T-cell receptor (TCR) signaling and CD28 costimulation induced cell cycle arrest in human T cells. VIP blocked G₁/S transition and inhibited the synthesis of cyclins D3 and E and the activation of the cyclin-dependent kinases (CDKs) cdk2 and cdk4. This effect was accompanied by maintenance of threshold levels of the CDK inhibitor p27^kip1 and impairment of phosphatidylinositol 3-kinase (PI3K)-Akt signaling. Inhibition of interleukin 2 (IL-2) transcription and downregulation of signaling through NFAT, AP-1, and Ras-Raf paralleled the VIP-induced cell cycle arrest. Noteworthy from a functional point of view is the fact that VIP-treated T cells show a regulatory phenotype characterized by high expression of CD25, cytotoxic-T-lymphocyte-associated protein 4 (CTLA4), and Forkhead box protein 3 (FoxP3) and potent suppressive activities against effector T cells. CTLA4 appears to be critically involved in the generation and suppressive activities of VIP-induced T_reg. Finally, cyclic AMP (cAMP) and protein kinase A (PKA) activation seems to mediate the VIP-induced cell cycle arrest and T_reg generation.

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This work was supported by the Spanish Ministry of Science and Innovation, Junta de Andalucia, and Spanish Collaborative Network on Multiple Sclerosis (ISCIII-RETICS-REEM).