VIP1 and VIP2 receptors but not PVR1 mediate the effect of VIP/PACAP on cytokine production in T lymphocytes.

Neuropeptides such as VIP and PACAP produced or released within the lymphoid microenvironment modulate the immune response through their effect on immune cells bearing specific receptors. In response to antigenic stimulation, CD4+ T cells, and to a lesser degree CD8+ T cells, produce cytokines that play essential roles in the initiation and amplification of various immune responses. VIP/PACAP downregulate the expression of a variety of cytokines such as IL-2, IL-4, and IL-10, by directly affecting the cytokine-producing T cells. Since three types of receptors, PVR1 (the PACAP-preferring receptor), PVR2 (VIP1), and PVR3 (VIP2) bind PACAP/VIP, this study investigated the expression of these receptors in murine T lymphocytes and their role in mediating the inhibition of cytokines. VIP1 and VIP2 agonists, but not PVR1 agonists, inhibit IL-2, IL-4, and IL-10 production, and VIP1 and VIP2, but not PVR1 mRNA, were identified in purified CD4+ and CD8+ splenic T cells. In addition, immunofluorescence studies confirmed the presence of VIP1 and VIP2 on CD4+ and CD8+ T cells. These results indicate that both subsets of peripheral T lymphocytes express VIP1 and VIP2, but not PVR1 receptors, and that the inhibitory effect of VIP/PACAP on IL-2 and IL-10 production is mediated by both VIP1 and VIP2 receptors.