Enhanced delayed-type hypersensitivity and diminished immediate-type hypersensitivity in mice lacking the inducible VPAC₂ receptor for vasoactive intestinal peptide

Vasoactive intestinal peptide (VIP) and its G protein-coupled receptors, VPAC₁R and VPAC₂R, are prominent in the immune system and regulate many aspects of T cell-dependent immunity. In mouse T cells, VPAC₁R is expressed constitutively, whereas VPAC₂R is induced by immune stimuli. VPAC₂R-null (VPAC₂R^-/-) 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 VPAC₂R-null mice compared with age- and sex-matched wild-type mice. In contrast, generation of IgE anti-hapten antibodies and active cutaneous anaphylaxis were ≥70% lower in VPAC₂R-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-γ (mean = 3-fold), and lower levels of IL-4 (mean = one-fifth) in VPAC₂R-null mice than wild-type controls. Loss of VIP-VPAC₂R 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.