VASOACTIVE-INTESTINAL-PEPTIDE ENHANCEMENT OF ANTIGEN-INDUCED DIFFERENTIATION OF A CULTURED LINE OF MOUSE THYMOCYTES

The prominence of vasoactive intestinal peptide (VIP) in rodent thymic neurons suggested that this potent mediator of T cell functions may a lter developmental responses of thymocytes to T cell receptor (TCR) -d ependent stimulation, CD4(+)8(+) DPK cells derived from a thymic lymph oma of a TCR transgenic mouse respond to pigeon cytochrome C (PCC) ant igen in association with distinct I-E MHC II haplotypes on antigen-pre senting cells (APCs) by differentiating into CD4(+)8(-) T cells, The s pecific recognition of VIP by two types of homologous C-protein-couple d receptors (VIPR1 and VIPR2) on DPK cells was attributable predominan tly to VIPR1 before and to VIPR2 after exposure to APCs and PCC, as as sessed by quantification of the respective mRNAs, PCC-evoked different iation of DPK cells was enhanced significantly by 1 to 100 nM VIP afte r 3 to 4 days, The effects of VIP analogs with VIPR type selectivity i mplied that VIP enhancement of differentiation of DPK cells was mediat ed principally by VIPR2, Differential reduction in the expression of e ach type of VIPR by transfection of DPK cells with plasmids encoding t he respective antisense mRNAs confirmed the central role of VIPR2 in V IP-enhanced conversion to CD4(+)8(-) T cells. The suppression of DPK c ell differentiation by inhibitors of adenylyl cyclase and protein kina se A suggested a transductional role for VIP-elicited increases in [cA MP](i). That the changes in frequency of CD4(+)8(+) and CD4(+)8(-) DPK cells reflected principally differentiation was supported by the lack of consistent differences between the two subsets in the effects of V IP and VIPR2 agonist on cell number, viability, apoptosis, and prolife ration, VIP may be one endogenous mediator that explains the unique th ymic microenvironment for topographically specific development of T ce lls.