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Vasoactive Intestinal Peptide Maintains the Nonpathogenic Profile of Human Th17-Polarized Cells

Abstract

The cytokine microenvironment modulates CD4 T cell differentiation causing the shift of naïve CD4 T cells into different cell subsets. This process is also regulated by modulators such as vasoactive intestinal peptide (VIP), a neuropeptide with known immunomodulatory properties on CD4 T cells that exert this action through specific receptors, vasoactive intestinal peptide receptor (VPAC)1 and VPAC2. Our results show that the pattern of VIP receptors expression ratio is modified during Th17 differentiation. In this report, we evaluate the capacity of VIP to modulate naïve human cells into Th17 cells in vitro by analyzing their functional phenotype. The presence of VIP maintains the nonpathogenic profile of Th17-polarized cells, increases the proliferation rate, and decreases their Th1 potential. VIP induces the upregulation of the STAT3 gene interaction with the VPAC1 receptor during the onset of Th17 differentiation. Moreover, RAR-related orphan receptor C (RORC), RAR-related orphan receptor A (RORA), and interleukin (IL)-17A genes are upregulated in the presence of VIP through interaction with VPAC1 and VPAC2 receptors. Interestingly, VIP induces the expression of the IL-23R gene through interaction with the VPAC2 receptor during the expansion phase. This is the first report that describes the differentiation of naïve human T cells to Th17-polarized cells in the presence of VIP and demonstrates how this differentiation regulates the expression of the VIP receptors.

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Acknowledgments

This work was supported by the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III (PI11/00195, PI12/00758 and RETICS RD08/0075, RD12/0009/0002) within VI PNDE I+D+I by FEDER funds from EU and S2010/BMD-2350 from Comunidad Autónoma de Madrid (CAM) and by grants from the ISCIII to RJ and MC, and the FPI grants from Ministerio de Economía y Competitividad to SPG. Thank you to the Transfusion Center of CAM and healthy donors for human cord blood samples.

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Correspondence to Yasmina Juarranz.

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Rosa P. Gomariz and Yasmina Juarranz share senior authorship.

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Jimeno, R., Leceta, J., Martínez, C. et al. Vasoactive Intestinal Peptide Maintains the Nonpathogenic Profile of Human Th17-Polarized Cells. J Mol Neurosci 54, 512–525 (2014). https://doi.org/10.1007/s12031-014-0318-3

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Keywords

  • Th differentiation
  • Th17
  • VIP
  • VPAC receptors