Adaptors and Molecular Scaffolds in Immune Cell Signaling

LAT and SLP-76 are expressed in T cells, monocytes, platelets, basophils, and mast cells, but they are surprisingly absent in B cells. SLP-76 is required for receptor-induced degranulation in mast cells, and SLP-76-deficient mice undergo severe hemorrhaging, possibly due to a defect in platelet degranulation (Pivniouk et al. 1998xPivniouk, V., Tsitsikov, E., Swinton, P., Rathbun, G., Alt, F.W., and Geha, R.S. Cell. 1998; 94: 229–238Abstract | Full Text | Full Text PDF | Scopus (300)See all ReferencesPivniouk et al. 1998). This shared pattern of adaptor expression in these cells may reflect a shared cellular function and/or a connection between LAT and other type III signaling modules. LAT and SLP-76 expression correlates with the use of the ζ chain by the TCR complex, and the related γ chain by the FcR e I complex in the recruitment of ZAP-70 and SYK. In this regard, it is possible that type III proteins such as LAT interact with other type III proteins such as the TCR ζ chain. In contrast, B cells use type I Ig α/β signaling proteins and fail to express LAT or SLP-76. Instead, these cells express a homolog termed BLNK/SLP-65. Although showing some sequence divergence, BLNK/SLP-65 and SLP-76 have the same overall architecture and an ability to bind PLC γ, Nck, and Vav (8xFu, C., Turck, C.W., Kurosaki, T., and Chan, A.C. Immunity. 1998; 9: 93–103Abstract | Full Text | Full Text PDF | Scopus (371)See all References, 24xWienands, J., Schweikert, J., Wollscheid, B., Hassan, J., Nielsen, P.J., and Reth, M. J. Exp. Med. 1998; 188: 791–795Crossref | Scopus (202)See all References). BLNK/SLP-65 also regulates NFAT transcription but may differ from SLP-76 in its inability to upregulate ERK activity (Fu et al. 1998xFu, C., Turck, C.W., Kurosaki, T., and Chan, A.C. Immunity. 1998; 9: 93–103Abstract | Full Text | Full Text PDF | Scopus (371)See all ReferencesFu et al. 1998).The growing family of novel immune-specific adaptors underscores the complexity of signaling networks in immune cells. Immune cells have supplemented the standard signaling proteins with an array of unique signaling proteins. Eight chains of the TCR ζ/CD3 complex, numerous coreceptors, immune-specific kinases, and an array of immune-specific adaptors are needed for T cell function. This complexity probably reflects the diversity of functions found in the immune system. Different adaptors and their combinatorial patterns of binding will almost certainly be found to produce differences in lymphokine expression. Combinatorial patterns may shift in response to different peptide ligands or be a fixed constellation in different T cell subsets (Th1 vs. Th2). Differential TCR recruitment of ZAP-70 in response to peptides of varying avidity will be reflected in the formation of different complexes, for example between SLP-76 and the associated Nck and Vav proteins. This in turn will result in the different degrees of receptor cross-linking. Different transcription factors in the IL-2 promoter (NF-AT, AP-1, and NF-κ B) are also likely to be influenced by different adaptor complexes. While SLP-76 is needed for NF-AT activity, other adaptors such as FYB/SLP-76 might favor AP-1 transcriptional activity. The action of antagonistic peptides could be linked to negative regulatory elements such as Cbl in a LAT/SLP-76 multiprotein aggregate. Coreceptors such as CD28 that provide a necessary second signal in the T cell response might now be found linked to LAT or other adaptors. Future studies will provide an exciting scenario in unraveling the interconnections responsible for different immune responses.