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).
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 (VPAC1) or activation-induced type 2 G protein-coupled receptor (VPAC2). Recently, a short-deletion (SD) splice variant of mouse VPAC2 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) VPAC2 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 VPAC2 were studied in VPAC2-low D10G4.1 model Th2 cell transfectants individually expressing the respective types of VPAC2 equally. WT and SD VPAC2 Th2 cell transfectants secreted equal amounts of VIP. WT VPAC2 transfectants generated more IL-4 than did SD VPAC2 transfectants, and this increment was dependent on endogenous VIP. Exogenous VIP further increased IL-4 production by WT VPAC2 transfectants but decreased IL-4 production by SD VPAC2 transfectants. Cotransfection of the two constructs diminished VIP enhancement of IL-4 production seen with WT VPAC2 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 VPAC2 determines the net effect of VIP on IL-4 generation by activated Th2 cells.
Huang
Mei-Chuan
MC
Department of Medicine and Microbiology-Immunology, University of California, San Francisco, CA 94143, USA.
Miller
Allison L
AL
Wang
Wengang
W
Kong
Yvonne
Y
Paul
Sudhir
S
Goetzl
Edward J
EJ
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D017353:Gene Deletion; D006801:Humans; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*
D012333:RNA, Messenger; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D015847:Interleukin-4; D014660:Vasoactive Intestinal Peptide