Abstract

Vasoactive intestinal peptide (VIP) and its type I and II G protein-coupled receptors, VPAC1R and VPAC2R, are prominent in the mammalian immune system and regulate many aspects of innate and adaptive immunity. VPAC1R is expressed constitutively by T cells, whereas VPAC2R on T cells is induced and repressed by numerous immune factors. Constitutive expression of VPAC2R selectively in CD4+ T cells of transgenic (TG) C57BL/6 mice evokes production of more Th2-type IL-4 and IL-5, and less Th1-type IFNgamma after T cell receptor (TCR) activation with consequent in vivo elevation of blood IgE, IgG1 and eosinophils. CD4+ T cell-VPAC2 R TG mice show enhanced IgE antibody responses and cutaneous immediate-type hypersensitivity, and depressed delayed- type hypersensitivity (DTH). In contrast, VPAC2 Rnull (K/O) C57BL/6 mice exhibit significantly heightened hapten-evoked cutaneous DTH, suppressed generation of IgE anti-hapten antibodies and depressed active cutaneous anaphylaxis, as a result of production of more Th1-type IFN-gamma and less Th2-type IL-4 and IL-5 after TCR activation. The higher than normal Th2/Th1 ratio for VPAC2R-TG mice and higher than normal Th1/Th2 ratio for VPAC2R-null mice will be elucidated by studies to: 1) assess diverse ex vivo functional responses to VIP of CD4+ and CD8+ T cells from VPAC2R-null mice with only VPAC1Rs and from VPAC2R-TG mice with a vast predominance of VPAC2Rs; 2) delineate roles of endogenous VIP-VPACR systems in development and activation of T cells in VPAC2R-null and VPAC2R-TG mice using existing anti-VIP peptidolytic antibodies to eliminate VIP and newly-developed antagonistic anti-VPAC1R and anti-VPAC2R rat MoAbs to block each VPACR at different stages of maturation; 3) analyze critical transcriptional and signaling pathways by which the VIP-VPAC2R system differentially regulates lineage commitment of Th1 and Th2 cells; and 4) investigate effects of VIP-VPAC2R-mediated skewing of Th1/Th2 balance on host defense and immunopathogenic reactions in VPAC2R-null and VPAC2R-TG mice. VPAC2R agonist drugs thus are expected to augment mobilization of CD4+ T cells in normal immune responses, whereas VPAC2R antagonists may contribute to termination of hypersensitivity reactions and correction of T cell immune deficiencies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI029912-14
Application #
6846029
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Johnson, David R
Project Start
1992-02-01
Project End
2008-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
14
Fiscal Year
2005
Total Cost
$303,000
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Yadav, Mahesh; Huang, Mei-Chuan; Goetzl, Edward J (2011) VPAC1 (vasoactive intestinal peptide (VIP) receptor type 1) G protein-coupled receptor mediation of VIP enhancement of murine experimental colitis. Cell Immunol 267:124-32
Yadav, Mahesh; Goetzl, Edward J (2008) Vasoactive intestinal peptide-mediated Th17 differentiation: an expanding spectrum of vasoactive intestinal peptide effects in immunity and autoimmunity. Ann N Y Acad Sci 1144:83-9
Goetzl, Edward J; Chan, Robert C; Yadav, Mahesh (2008) Diverse mechanisms and consequences of immunoadoption of neuromediator systems. Ann N Y Acad Sci 1144:56-60
Yadav, Mahesh; Rosenbaum, Jennifer; Goetzl, Edward J (2008) Cutting edge: vasoactive intestinal peptide (VIP) induces differentiation of Th17 cells with a distinctive cytokine profile. J Immunol 180:2772-6
Goetzl, Edward J (2006) Hypothesis: VPAC G protein-coupled receptors for vasoactive intestinal peptide constitute a dynamic system for signaling T cells from plasma membrane and nuclear membrane complexes. Regul Pept 137:75-8
Miller, Allison L; Verma, Deepti; Grinninger, Carola et al. (2006) Functional splice variants of the type II G protein-coupled receptor (VPAC2) for vasoactive intestinal peptide in mouse and human lymphocytes. Ann N Y Acad Sci 1070:422-6
Huang, Mei-Chuan; Miller, Allison L; Wang, Wengang et al. (2006) Differential signaling of T cell generation of IL-4 by wild-type and short-deletion variant of type 2 G protein-coupled receptor for vasoactive intestinal peptide (VPAC2). J Immunol 176:6640-6
Voice, Julia; Donnelly, Samantha; Dorsam, Glenn et al. (2004) c-Maf and JunB mediation of Th2 differentiation induced by the type 2 G protein-coupled receptor (VPAC2) for vasoactive intestinal peptide. J Immunol 172:7289-96
Grinninger, Carola; Wang, Wengang; Oskoui, Kaveh Bastani et al. (2004) A natural variant type II G protein-coupled receptor for vasoactive intestinal peptide with altered function. J Biol Chem 279:40259-62
Voice, Julia K; Grinninger, Carola; Kong, Yvonne et al. (2003) Roles of vasoactive intestinal peptide (VIP) in the expression of different immune phenotypes by wild-type mice and T cell-targeted type II VIP receptor transgenic mice. J Immunol 170:308-14

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