Suppression of antigen-specific Th2 cell-dependent IgM and IgG1 production following norepinephrine depletion in vivo.

The mechanism by which the Th2 cell-dependent Ab response is modulated by the sympathetic neurotransmitter norepinephrine (NE) was investigated. Our model system used the severe combined immunodeficient (scid) mouse that was depleted of NE with 6-hydroxydopamine before reconstitution with a clone of beta2-adrenergic receptor (beta2AR)neg KLH-specific Th2 cells and resting trinitrophenyl (TNP)-specific beta2ARpos B cells enriched from the spleens of unimmunized mice. Following challenge with TNP-keyhole limpet hemocyanin (KLH), Ab production in these mice was hapten-, carrier-, and allotype-specific as well as MHC restricted. Depletion of NE resulted in a 50-75% suppression of the primary anti-TNP IgM response compared with that of NE-intact controls, while the secondary IgM response returned to control levels. In contrast, both the primary and secondary anti-TNP IgG1 responses were suppressed by 85 and 40%, respectively. Using NE-intact mice exposed to either a betaAR- or alphaAR-selective antagonist, the effect of NE on the Ab response was shown to be mediated by the betaAR. In addition, administration of a beta2AR-selective agonist to NE-depleted mice partially reversed the suppressed Ab response that resulted from NE depletion. Expression of the beta2AR on TNP-specific B cells was confirmed by radioligand binding, immunofluorescence, and cAMP analysis. Also, while splenic histology was comparable in NE-intact and NE-depleted mice before Ag exposure, follicle expansion and germinal center formation were suppressed in NE-depleted mice after Ag exposure. Taken together, these results suggest that NE stimulation of the beta2AR expressed on B cells is necessary for the maintenance of an optimal primary and secondary Th2 cell-dependent Ab response in vivo.