Vasoactive intestinal peptide (VIP) released from some neurons and T cells affects T cell migration, cytokine generation, and other functions by binding to constitutively expressed type 1 G protein-coupled receptor (VPAC(1)) or activation-induced type 2 G protein-coupled receptor (VPAC(2)). Recently, a short-deletion (SD) splice variant of mouse VPAC(2) that lacks 14 amino acids at the end of the last transmembrane domain has been identified in T cells and shown to resemble wild-type (WT) VPAC(2) in affinity of VIP binding but to differ by lack of signaling of T cell adenylyl cyclase, migration, and IL-2 secretion. As Th2 cells are the principal source of immune VIP and have the greatest functional responses to VIP, the differences in signals transduced by WT and SD VPAC(2) were studied in VPAC(2)-low D10G4.1 model Th2 cell transfectants individually expressing the respective types of VPAC(2) equally. WT and SD VPAC(2) Th2 cell transfectants secreted equal amounts of VIP. WT VPAC(2) transfectants generated more IL-4 than did SD VPAC(2) transfectants, and this increment was dependent on endogenous VIP. Exogenous VIP further increased IL-4 production by WT VPAC(2) transfectants but decreased IL-4 production by SD VPAC(2) transfectants. Cotransfection of the two constructs diminished VIP enhancement of IL-4 production seen with WT VPAC(2) alone by preventing increases in nuclear levels of the requisite transcription factors c-Maf and Jun B. Thus the ratio of two forms of T cell VPAC(2) determines the net effect of VIP on IL-4 generation by activated Th2 cells.