CROSS-LINKING CD28 LEADS TO ACTIVATION OF 70-KDA S6 KINASE

Proliferation of T lymphocytes in response to antigen/MHC complexes is dependent upon the presence of a co-stimulatory signal; in its absenc e,T cells are rendered unresponsive to specific antigen. CD28 is a T c ell surface glycoprotein that acts as a co-stimulatory molecule when c ombined with signals initiated by the T cell receptor-CD3 complex. Whi le the biochemical signaling events following CD28 stimulation are sti ll poorly defined, monoclonal antibodies (mAb) directed against CD28 h ave been shown to transduce a variety of early signals that are differ ent in the presence of cross-linking antibody or the presence of phorb ol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PK C). Stimulation of human T cells with cross-linked anti-CD28 mAb alone resulted in the activation of 70-kDa (p70) S6 kinase, a rapamycin-sen sitive serine/threonine kinase that is believed to be important for ce ll cycle progression. Activation of p70 S6 kinase through CD28 was inh ibited by rapamycin. Activation of p70 S6 kinase also increased in res ponse to cross-linked CD3, but followed a more rapid time course than activation via CD28. Cyclosporin A and FK506 had no effect on p70 S6 k inase activity initiated via either pathway. The combination of cross- linked CD28 and cross-linked CD3 had no more than an additive effect o n the induction of p70 S6 kinase activity. Thus, recruitment of p70 S6 kinase activity appears to represent a common signal transduction eve nt shared by both the CD28 and CD3 pathways of T cell activation.