Editors' ChoiceImmunology

CD28, A Receptor in Its Own Right

Science's STKE  08 Jan 2002:
Vol. 2002, Issue 114, pp. tw9
DOI: 10.1126/stke.2002.114.tw9

CD28 has been characterized as a coreceptor for the T cell receptor (TCR) and as responsible for providing the costimulatory signal required for T cell activation. Raab et al. provide evidence that CD28 is a receptor independent of the TCR and can initiate signaling events without concomitant TCR ligation. The initial studies used Jurkat cells cotransfected with the adaptor VAV and the adaptor SLP-76 and measured the stimulation of expression of reporter genes with the promoters for interleukins (ILs) IL-2 or IL-4 in response to CD28 activation in the absence of TCR ligation. Similar experiments using human T cells heterogenously expressing VAV or SLP-76 showed that activation of CD28 with an antibody ligand or with Chinese hamster ovary cells expressing the native CD28 ligand CD80 stimulated IL-2 secretion. Analysis of the tranfected Jurkat cells or the human T cells showed that the SLP-76 and VAV complexes were formed in the membrane fraction and phosphorylated with highest efficiency in the membrane fraction after CD28 activation. Signaling from CD28 was also tested in nonlymphoid cells by transfection of CD28, VAV, SLP-76, and a green fluorescent protein (GFP)-labeled NFAT into COS cells. Again CD28 activation stimulated the translocation of GFP-NFAT into the nucleus in cells expressing all four proteins: CD28, VAV, SLP-76, and GFP-NFAT. Cotransfection experiments in Jurkat cells with VAV, SLP-76, and the guanosine triphosphatase Rac1 showed that Rac1 potentiated CD28-stimulated expression of the IL-2 reporter gene. This result prompted Raab et al. to test whether CD28 activation could induce actin reorganization, because of the known regulation of the cytoskeleton by Rac, and, indeed, CD28 activation in the presence of VAV and SLP-76 produced capping and F-actin polymerization. Thus, CD28 appears able to signal independently from TCR activation, at least in the presence of exogenous VAV and SLP-76, both for regulating gene expression and for cytoskeletal reorganization.

M. Raab, S. Pfister, C. Rudd, CD28 signaling via VAV/SLP76 adaptors: Regulation of cytokine transcription independent of TCR ligation. Immunity 15, 921-933 (2001). [Online Journal]