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 for maintaining peripheral tolerance and for limiting an ongoing immune response. AICD is initiated by Ag re-engagement of the TCR and is mediated through Fas/Fas ligand (FasL) interactions. Vasoactive intestinal peptide (VIP) and the structurally related pituitary adenylate cyclase-activating polypeptide (PACAP) are two multifunctional neuropeptides present in the lymphoid microenvironment that act primarily as anti-inflammatory agents. In the present study we investigated whether VIP and PACAP affect AICD in mature peripheral T cells and T cell hybridomas. VIP and PACAP reduce in a dose-dependent manner anti-CD3-induced apoptosis in Con A/IL-2-preactivated peripheral T cells and the murine T hybridomas 2B4.11 and A1.1. A functional study demonstrates that the inhibition of AICD is achieved through the inhibition of activation-induced FasL expression at protein and mRNA levels. VIP/PACAP-mediated inhibition of both AICD and FasL expression is mediated through the specific receptors VPAC1 and VPAC2. Of obvious biological significance is 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 FasL-mediated T cell cytotoxicity.
Delgado
M
M
Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA.
Ganea
D
D
D000818:Animals; D000941:Antigens / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology*; D019898:Autocrine Communication / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D053222:Fas Ligand Protein; D005260:Female; D006825:Hybridomas / Q000166:cytology / Q000276:immunology; D007106:Immune Sera / Q000494:pharmacology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D009479:Neuropeptides / Q000502:physiology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018005:Receptors, Vasoactive Intestinal Peptide / Q000502:physiology; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014660:Vasoactive Intestinal Peptide / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism*
C495402:Adcyap1 protein, mouse; D000941:Antigens; D017252:CD3 Complex; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007106:Immune Sera; D008024:Ligands; D008562:Membrane Glycoproteins; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018005:Receptors, Vasoactive Intestinal Peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D019014:fas Receptor; D014660:Vasoactive Intestinal Peptide