STIMULATION VIA THE CD28 MOLECULE - REGULATION OF SIGNALING, CYTOKINEPRODUCTION AND CYTOKINE RECEPTOR EXPRESSION

In the present article are reviewed the main experimental evidences co ncerning the costimulatory function of CD28 in T cell activation. Huma n CD28 molecule is a 44Kd homodimeric glycoprotein expressed by most m ature T lymphocytes. CD28/ B7 ligand/receptor system in the presence o f other stimuli, such as CD3/TCR, is critical for inducing both Th1 an d Th2-specific lymphokines and monocytic cytokines. CD28 pathway acts on cytokine gene expression through a transcriptional and post-transcr iptional regulation (by increasing the transcript stability) and could also upregulate the expression of interleukin receptors such as the t hree chains alpha, beta, gamma of the IL-2 receptor. At least two phys iological ligands of CD28 exist, namely B7.1/CD80 and B7.2/B70, belong ing to the immunoglobulin supergene family and sharing some structural homologies. The ligands differ in tissue distribuition and in the kin etics of expression on activated B cells. To date it has to be clarifi ed if the two molecules are interchangeable between each other, if the re is a synergy between the effect of the ligands in activating CD28 p athway and finally if the different expression on antigen presenting c ells and the differential expression kinetics are critical for their p hysiological role. CD28 activation generates multiple intracellular si gnal transduction pathways. CD28/B7.1 interaction is able to activate intracellular protein tyrosine kinase (PTK) activities. A substrate fo r CD28-induced PTK acitivity is PLC gamma whose activation results in release of inositol phosphates and diacylglycerol. Moreover B7.1 is ab le to induce tyrosine phosphorylation of CD28 which becomes physically associated with the 85 KDa subunit of P13 kinase. CD28 mutants in P13 K binding site are unable to associate with the enzyme as well as to produce IL-2 when stimulated. In addition ligation of CD28 by monoclon al antibody (mAb) activates the p21Ras protein and induce Ras dependen t events. Thus, some of the second messengers induced via CD28 are dis tinct from (P13 kinase binding) some other strictly connected with CD3 /TCR (ras and PLC gamma activation).