CD28 co-stimulatory regimes differ in their dependence on phosphatidylinositol 3-kinase: common co-signals induced by CD80 and CD86

• Published in: International immunology 1996-10, Vol.8 (10), p.1609-1616
• Main Authors: Cefai, Daniel, Cai, Yun-Cai, Hu, Hui, Rudd, Christopher
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - metabolism; Antibodies, Monoclonal - pharmacology; Antigens, CD - pharmacology; B7-1 Antigen - pharmacology; B7-2 Antigen; CD28 Antigens - immunology; CD28 Antigens - metabolism; CD28 Antigens - pharmacology; CHO Cells; Cricetinae; Lymphocyte Activation - drug effects; Membrane Glycoproteins - pharmacology; Phosphatidylinositol 3-Kinases; Phosphotransferases (Alcohol Group Acceptor) - physiology; Signal Transduction - drug effects; Signal Transduction - immunology
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/8.10.1609

CD80 (B7–1) and CD86 (B7–2) ligation of CD28 provide co-stimulatory signals required for optimal lymphokine production in response to TCRÇ-CD3 ligation. CD28 binds to several intracellular proteins including phosphatidylinositol 3-kinase (PI3-kinase), the tyrosine kinase ITK and the growth factor receptor-bound protein/Son of Sevenless (GRB-2/S0S) complex. Previously, we showed that TCRÇ-CD3 and CD28 co-stimulation required PI3-kinase binding to the pYMNM motif of the cytoplasmic domain of the co-receptor. In this study, we have investigated whether CD28-associated PI3-kinase is required for CD80 and CD86 co-stimulation, as well as in co-signaling that involves different primary signals (i.e. TCRÇ-CD3 versus phorbol ester/ionomycin). In the presence of anti-CD3, ligation of CD28 by both CD80 and CD86 was found to induce PI3-kinase recruitment and IL-2 production. Furthermore, mutations at Y-191 and M-194 within the pYMNM motif blocked the ability of both ligands to induce IL-2. CD80 and CD86 therefore share a common signaling pathway leading to IL-2 production. By contrast, CD28 mediated co-stimulation involving receptor ligation plus phorbol ester/ionomycin induced IL-2 independent of PI3-kinase binding to CD28. These data indicate that TCRÇ-CD3-dependent CD80 and CD86 co-signaling requires PI3-kinase binding to the CD28pYMNM motif, while phorbol ester and ionomycin can bypass this requirement in CD28 co-stimulation.