Richard V Parry, Department of Pharmacy & Pharmacology, University of Bath, Bath, UK
Stephen G Ward, Department of Pharmacy & Pharmacology, University of Bath, Bath, UK
Published online: September 2005
DOI: 10.1038/npg.els.0001184
T-lymphocyte activation refers to the set of biochemical events triggered by interaction of the T-cell antigen receptor with foreign antigen. Activation culminates in the secretion of IL-2, an autocrine growth factor for T cells.
Keywords: TCR; SMAC; phosphoinositides
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Figure 1. CD3/CD28 regulation of the NFB pathway. CD28-responsive regions of the IL-2 promoter encode binding sites for NFB. Both CD3 and CD28 contribute to the regulation of PKC. CARMA1 also known as CARD11 is a scaffold molecule that interacts with PKC, Bcl-10 and IB kinase (IKK). Phosphorylated Bcl-10 dimerizes mucosal associated lymphoid tissue protein 1 (MALT1) activating IB kinases. NFB dimers are normally bound to inhibitory IBs and retained in the cytoplasm. Phosphorylation of IB initiates its ubiquitination and degradation freeing NFB to translocate to the nucleus.
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Figure 2. Signalling scaffolds downstream of the TCR. Ligation of the T-cell antigen receptor (TCR) is followed by tyrosine phosphorylation of linker for activated T cells (LAT) and Src-homology 2 domain containing leucocyte protein of 76 kDa (SLP-76). In addition to triggering proximal signalling events TCR ligation precipitates a dynamic reorganization of cortical actin. This enables a complex programme of interaction between a T cell and an antigen-presenting cell (APC) ultimately resulting in a mature immunological synapse or supramolecular activation complex (SMAC). LAT plays a central role in linking the TCR to cytoskeletal reorganization interfacing to SLP-76 via Grb-2-related adaptor downstream of Shc (GADS). SLP-76 interacts with three adaptors that are implicated in cytoskeletal remodelling, namely Vav, Nck and adhesion and degranulation-promoting adaptor protein (ADAP).
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Figure 3. LAT couples the TCR to downstream signals. The adaptor molecule linker for activated T cells (LAT) is tyrosine-phosphorylated following TCR ligation. Tyrosine-phosphorylated LAT binds to the Grb-2/Sos complex to regulate Ras signalling. LAT also binds PLC that hydrolyses PtdIns(4,5)P
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| Further Reading | |
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