Complex Complexes: Signaling at the TCR

The focus of this review has been on the complexity of biochemical events at a very proximal position in the TCR signaling cascade. A number of proteins and protein–protein interactions have been described. It should be noted that the function of many of these proteins (e.g., Vav, Cbl, PI3K, and SLP-76) remains to be defined. Likewise, a full accounting of all of the proteins involved in signaling complexes remains to be performed. The reader should know that extensive analysis of the pathways further downstream in the T cell and in other systems suggests that complexity exists at these levels too (Cantrell 1996xT cell antigen receptor signal transduction pathways. Cantrell, D. Annu. Rev. Immunol. 1996; 14: 259–274Crossref | PubMed | Scopus (551)See all ReferencesCantrell 1996). For example, Ras is likely to be only one of the many small G proteins involved in transduction events. Similarly, the well-known ERK kinase, which is most certainly involved in TCR-coupled events, is only one of several related serine/threonine kinases involved in signaling via TCR and other surface receptors. The complexity of the transcriptional machinery assembled at each lymphokine promoter is also well known. We also acknowledge that we have focused almost entirely on TCR-mediated signaling. Biochemical signals arising from engagement of coreceptors, costimulatory receptors, and adhesion molecules are also integrated to give the complex cellular response. Moreover, complex protein–protein interactions driven by these receptors are likely to be found. T cell activation can no longer be described only in terms of simple linear or even branching biochemical steps, but instead must also be thought of as a complex web of associated proteins.Several observations indicate that careful attention to nuances in the T cell signaling pathways is warranted. Activation of T cells with peptides or MHC molecules bearing subtle changes in sequence, so-called altered peptide ligands, results in dramatic differences in TCRζ and ZAP-70 tyrosine phosphorylation and ZAP-70 activity (64xPartial T cell signaling (altered phospho-ζ and lack of ZAP-70 recruitment in APL-induced T cell anergy) . Sloan-Lancaster, J, Shaw, A.S, Rothbard, J.B, and Allen, P.M. Cell. 1995; 79: 913–922Abstract | Full Text PDF | Scopus (541)See all References, 43xζ phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists. Madrenas, J, Wange, R.L, Wang, J.L, Isakov, N, Samelson, L.E, and Germain, R.N. Science. 1995; 267: 515–518Crossref | PubMedSee all References). Similarly, T cell activation schemes that result in anergic T cells fail to induce Ras and ERK activation (40xBlocked signal transduction to the ERK and JNK protein kinases in anergic CD4+ T cells. Li, W, Whaley, C.D, Mondino, A, and Mueller, D.L. Science. 1996; 271: 1272–1276Crossref | PubMedSee all References, 21xBlocked Ras activation in anergic CD4+ T cells. Fields, P.E, Gajewski, T.F, and Fitch, F.W. Science. 1996; 271: 1276–1278Crossref | PubMedSee all References). These examples are likely the first of many instances of variable biochemical responses to receptor engagement. Subtle changes in biochemical signals and in the composition of signaling complexes may have profound effects on cellular physiology. The existence of highly regulated signaling pathways offers the possibility of great flexibility of response to the T cell.