CD28 - A SIGNALING PERSPECTIVE

CD28 and the related molecule cytotoxic T lymphocyte-associated molecu le-4 (CTLA-4), together with their natural ligands B7.1 and B7.2, have been implicated in the differential regulation of several immune resp onses, CD28 provides signals during T cell activation which are requir ed for the production of interleukin 2 and other cytokines and chemoki nes, and it has also been implicated in the regulation of T cell anerg y and programmed T cell death, The biochemical signals provided by CD2 8 are cyclosporin A-resistant and complement those provided by the T c ell antigen receptor to allow full activation of T cells. Multiple sig nalling cascades which may be independent of, or dependent on, protein tyrosine kinase activation have been demonstrated to be activated by CD28, including activation of phospholipase C, p21(ras), phosphoinosit ide 3-kinase, sphingomyelinase/ceramide and 5-lipoxygenase. The relati ve contributions of these cascades to overall CD28 signalling are stil l unknown, but probably depend on the state of activation of the T cel l and the level of CD28 activation, The importance of these signalling cascades (in particular the phosphoinositide 3-kinase-mediated cascad e) to functional indications of CD28 activation, such as interleukin 2 gene regulation, has been investigated using pharmacological and gene tic manipulations. These approaches have demonstrated that CD28-activa ted signalling cascades regulate several transcription factors involve d in interleukin 2 transcriptional activation. This review describes i n detail the structure and expression of the CD28 and B7 families, the functional outcomes of CD28 ligation and the signalling events that a re thought to mediate these functions.