Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit antigen-induced apoptosis of mature T lymphocytes by inhibiting Fas ligand expression

Apoptosis in T and B lymphocytes is a major element controlling the immune response. The Ag-induced cell death (AICD) in T cells is a main mechanism f or maintaining peripheral tolerance and for limiting an ongoing immune resp onse. AICD is initiated by Ag re-engagement of the TCR and is mediated thro ugh Fas/Fas ligand (FasL) interactions. Vasoactive intestinal peptide (VIP) and the structurally related pituitary adenylate cyclase-activating polype ptide (PACAP) are two multifunctional neuropeptides present in the lymphoid microenvironment that act primarily as anti-inflammatory agents. In the pr esent study we investigated whether VIP and PACAP affect AICD in mature per ipheral T cells and T cell hybridomas. VIP and PACAP reduce in a dose-depen dent manner anti-CD3-induced apoptosis in Con A/IL-2-preactivated periphera l T cells and the murine T hybridomas 2B4.11 and A1.1. A functional study d emonstrates that the inhibition of AICD is achieved through the inhibition of activation-induced Fast expression at protein and mRNA levels. VIP/PACAP -mediated inhibition of both AICD and Fast expression is mediated through t he specific receptors VPAC1 and VPAC2. Of obvious biological significance i s the fact that VIP and PACAP prevent Ag-induced clonal deletion of CD4(+) T cells, but not that of CD8(+) T cells. By affecting FasL expression, VIP and PACAP may play a physiological role in both the generation of memory T cells and the inhibition of Fast-mediated T cell cytotoxicity.