Background: Vasoactive intestinal peptide (VIP) is a 3.3 kDa pleiotropic protein
with a broad expression profile that displays immune modulating activities. VIP
binds two G protein-coupled receptors called Vasoactive Intestinal Pepide/Pituitary
Adenylate Cyclase activating polypeptide receptor (VPAC) 1 and 2 that elicit multiple
downstream signaling molecules, including adenylate cyclase. VIP differentially regulates
over 300 genes in resting and activated murine CD4 T cells, and is chemotactic to
resting and Th2 effector T cells.
Objective: This study is focused on delineating which human VIP receptor, called
VPAC1 and VPAC2, controls T cell biology pertaining to gene expression, signaling
Method: To this end, we utilized human T cell lines known to exclusively express
VPAC1, (HuT-78) or VPAC2 (Molt-4) in an attempt to identify VIP-receptor mediated
changes in gene expression, signaling and chemotaxis.
Results: This research successfully demonstrated three major findings. First, malignant
or primary human T cells failed to differentially regulate any gene targets when treated
with VIP ligand as assessed by an Agilent whole human microarray. Second, despite
drastically different [cAMP]i profiles, both T cell lines responded similarly to VIP in
Boyden Chamber assays showing both chemorepulsion and chemoattraction at low versus
high VIP concentrations. Lastly, both T cell lines were equally sensitive to AC and
PKA inhibitors that blocked VIP-induced chemotaxis, but were differentially sensitive to
Conclusion: Collectively, these results indicate that VIP signaling in resting human T
cells is ineffective at altering mRNA expression changes, unlike their rodent counterparts,
but can influence similar chemotactic effects, possibly through different signaling
pathways elicited through VPAC1 versus VPAC2.