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International Immunology Advance Access originally published online on October 31, 2006
International Immunology 2006 18(12):1691-1700; doi:10.1093/intimm/dxl103
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© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Altered expression of vasoactive intestinal peptide receptors in T lymphocytes and aberrant Th1 immunity in multiple sclerosis

Wei Sun1,*, Jian Hong1,*, Ying C. Q. Zang1, Xin Liu1 and Jingwu Z. Zhang1,2

1 Department of Neurology, Baylor College of Medicine, Mail station NB302, One Baylor Plaza, Houston, TX 77030, USA
2 Joint Immunology Laboratory of Institute of Health Sciences and Shanghai Institute of Immunology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao-Tong University School of Medicine, Shanghai, China

Correspondence to: J. Z. Zhang; E-mail: jzang{at}bcm.tmc.edu

Vasoactive intestinal peptide (VIP) has a unique property of regulating Th1 and Th2 immunity of CD4+ T cells. In this study, we demonstrated, for the first time, that differential expression of VIP receptors and a compensatory mechanism directly affect the responsiveness of CD4+ T cells and their Th1 and Th2 properties to VIP. The expression of VIP receptor-1 (VPAC1) and VPAC2 in CD4+ T cells changed reciprocally in the context of the activation state. In activated CD4+ T cells of healthy individuals, markedly decreased VPAC1 expression was compensated for by increased expression of VPAC2 induced by T cell activation. In contrast, there was altered expression of VPAC2 in activated CD4+ T cells derived from multiple sclerosis (MS) patients, which rendered CD4+ T cells less responsive to VIP and skewed the system to a predominantly in a Th1 direction. Detailed characterization with agonist peptides of VIP showed that residues Met and Ser at positions 17 and 25 of VIP were critical to its regulatory properties through interaction with VAPC2. Furthermore, altered levels of VPAC2 expression in T cells of MS patients were not associated with single-nucleotide polymorphism in the encoding region of the VPAC2 gene but with gene regulation as characterized by a distinct DNA footprinting pattern in the promoter region of the VPAC2 gene in MS as compared with controls. This study has provided new evidence for an intrinsic mechanism associated with an aberrant, pro-inflammatory state of CD4+ T cells in MS.

Keywords: cytokines, multiple sclerosis, T cell activation, Th1 and Th2 immunity, vasoactive intestinal peptide

* These authors contributed equally to this work.

Transmitting editor: C. Paige


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M. Yadav, J. Rosenbaum, and E. J. Goetzl
Cutting Edge: Vasoactive Intestinal Peptide (VIP) Induces Differentiation of Th17 Cells with a Distinctive Cytokine Profile
J. Immunol., March 1, 2008; 180(5): 2772 - 2776.
[Abstract] [Full Text] [PDF]


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