Enhanced delayed-type hypersensitivity and diminished immediate-type hypersensitivity in mice lacking the inducible VPAC(2) receptor for vasoactive intestinal peptide.
Vasoactive intestinal peptide (VIP) and its G protein-coupled receptors, VPAC(1)R and VPAC(2)R, are prominent in the immune system and regulate many aspects of T cell-dependent immunity. In mouse T cells, VPAC(1)R is expressed constitutively, whereas VPAC(2)R is induced by immune stimuli. VPAC(2)R-null (VPAC(2)R(-/-)) mice on a C57BL/6 background are shown here to have normal basic immune characteristics, including serum Ig concentrations, blood levels of all leukocytes, and spleen number of total T cells (CD3(+)) and T cells bearing CD4, CD8, and CD28. Hapten-evoked cutaneous delayed-type hypersensitivity (DTH) was significantly enhanced in VPAC(2)R-null mice compared with age- and sex-matched wild-type mice. In contrast, generation of IgE anti-hapten antibodies and active cutaneous anaphylaxis were > or =70% lower in VPAC(2)R-null mice than in wild-type controls. Cytokine production by splenic CD4(+) T cells, stimulated with adherent anti-CD3 plus anti-CD28 antibodies, revealed higher levels of IL-2 (mean = 3-fold) and IFN-gamma (mean = 3-fold), and lower levels of IL-4 (mean = one-fifth) in VPAC(2)R-null mice than wild-type controls. Loss of VIP-VPAC(2)R maintenance of the normal ratio of Th2/Th1 cytokines thus leads to a state of enhanced DTH and depressed immediate-type hypersensitivity, which may alter both host defense and susceptibility to immune-mediated diseases.
Goetzl
E J
EJ
Department of Medicine and Immunology, University of California Medical Center, San Francisco, CA 94143-071, USA. egoetzl@itsa.ucsf.edu
Voice
J K
JK
Shen
S
S
Dorsam
G
G
Kong
Y
Y
West
K M
KM
Morrison
C F
CF
Harmar
A J
AJ
D000818:Animals; D006968:Hypersensitivity, Delayed / Q000276:immunology*; D006969:Hypersensitivity, Immediate / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018005:Receptors, Vasoactive Intestinal Peptide / Q000235:genetics / Q000276:immunology*; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014660:Vasoactive Intestinal Peptide / Q000276:immunology*
D018005:Receptors, Vasoactive Intestinal Peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D015847:Interleukin-4; D014660:Vasoactive Intestinal Peptide; D007371:Interferon-gamma