T-cell virtuosity in ‘‘knowing thyself”

Major Histocompatibility Complex (MHC) I and II and the αβ T-cell antigen receptor (TCRαβ) govern fundamental traits of adaptive immunity. They form a membrane-borne ligand-receptor system weighing host proteome integrity to detect contamination by nonself proteins. MHC-I and -II exhibit the “MHC-fold”, which is able to bind a large assortment of short peptides as proxies for self and nonself proteins. The ensuing varying surfaces are mandatory ligands for Ig-like TCRαβ highly mutable binding sites. Conserved molecular signatures guide TCRαβ ligand binding sites to focus on the MHC-fold (MHC-restriction) while leaving many opportunities for its most hypervariable determinants to contact the peptide. This riveting molecular strategy affords many options for binding energy compatible with specific recognition and signalling aimed to eradicated microbial pathogens and cancer cells. While the molecular foundations of αβ T-cell adaptive immunity are largely understood, uncertainty persists on how peptide-MHC binding induces the TCRαβ signals that instruct cell-fate decisions. Solving this mystery is another milestone for understanding αβ T-cells’ self/nonself discrimination. Recent developments revealing the innermost links between TCRαβ structural dynamics and signalling modality should help dissipate this long-sought-after enigma

CD28 costimulatory signal induces protein arginine methylation in T cells

Protein phosphorylation initiates signal transduction that triggers lymphocyte activation. However, other posttranslational modifications may contribute to this process. Here, we show that CD28 engagement induced protein arginine methyltransferase activity and methylation on arginine of several proteins, including Vav1. Methylation of Vav1 and IL-2 production were reduced by inhibiting S-adenosyl-L-homocysteine hydrolase, an enzyme that regulates cellular transmethylation. Methylated Vav1 was induced in human and mouse T cells and selectively localized in the nucleus, which suggested that this form marks a nuclear function of Vav1. Our findings uncover a signaling pathway that is controlled by CD28 that is likely to be important for T cell activation

T cell receptor for antigen induces linker for activation of T cell–dependent activation of a negative signaling complex involving Dok-2, SHIP-1, and Grb-2

Adaptor proteins positively or negatively regulate the T cell receptor for antigen (TCR) signaling cascade. We report that after TCR stimulation, the inhibitory adaptor downstream of kinase (Dok)-2 and its homologue Dok-1 are involved in a multimolecular complex including the lipid phosphatase Src homology 2 domain–containing inositol polyphosphate 5′-phosphatase (SHIP)-1 and Grb-2 which interacts with the membrane signaling scaffold linker for activation of T cells (LAT). Knockdown of LAT and SHIP-1 expression indicated that SHIP-1 favored recruitment of Dok-2 to LAT. Knockdown of Dok-2 and Dok-1 revealed their negative control on Akt and, unexpectedly, on Zap-70 activation. Our findings support the view that Dok-1 and -2 are critical elements of a LAT-dependent negative feedback loop that attenuates early TCR signal. Dok-1 and -2 may therefore exert a critical role in shaping the immune response and as gatekeepers for T cell tolerance

Quantitative Contribution of CD4 and CD8 to T Cell Antigen Receptor Serial Triggering

CD4 and CD8 are thought to function as coreceptors by binding to the cognate major histocompatibility complex (MHC) molecules recognized by the T cell antigen receptor (TCR) and initiating the signal transduction cascade. We report that during T cell–antigen-presenting cell interaction, triggered TCRs and coreceptors are downregulated and degraded with identical kinetics. This coordinated disappearance takes place whenever the TCR is triggered, even when the coreceptor does not engage the cognate MHC molecule and is the consequence of binding of the coreceptor-associated Lck to ZAP-70. The interaction of coreceptor and cognate MHC molecules is dispensable when T cells are stimulated by optimal ligands, but becomes crucial when suboptimal ligands are used. In the latter case the coreceptor increases the efficiency of TCR triggering without changing the activation threshold or the quality of the T cell response

Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination

Antigen recognition by the T-cell receptor (TCR) is a hallmark of the adaptive immune system. When the TCR engages a peptide bound to the restricting major histocompatibility complex molecule (pMHC), it transmits a signal via the associated CD3 complex. How the extracellular antigen recognition event leads to intracellular phosphorylation remains unclear. Here, we used single-molecule localization microscopy to quantify the organization of TCR–CD3 complexes into nanoscale clusters and to distinguish between triggered and nontriggered TCR–CD3 complexes. We found that only TCR–CD3 complexes in dense clusters were phosphorylated and associated with downstream signaling proteins, demonstrating that the molecular density within clusters dictates signal initiation. Moreover, both pMHC dose and TCR–pMHC affinity determined the density of TCR–CD3 clusters, which scaled with overall phosphorylation levels. Thus, TCR–CD3 clustering translates antigen recognition by the TCR into signal initiation by the CD3 complex, and the formation of dense signaling-competent clusters is a process of antigen discrimination

T cell activation and the cytoskeleton

Ligation of the T cell antigen receptor (TCR) stimulates protein tyrosine kinases (PTKs), which regulate intracellular calcium and control the activity of protein kinase C (PKC) isozymes. PTKs activated by antigen receptors and costimulatory molecules also couple to phosphatidylinositol-3 kinase (PI3K) and control the activity of Ras- and Rho-family GTPases. T cell signal transduction is triggered physiologically by antigen in the context of antigen presenting cells (APC). The formation of stable and prolonged contacts between T cells and APCs is not necessary to initiate T cell signaling but is required for effective T cell proliferation and differentiation. The stabilization of the T cell/ APC conjugate is regulated by intracellular signals induced by antigen receptors and costimulators. These coordinate the regulation of the actin and microtubule cytoskeleton and organize a specialized signaling zone that allows sustained TCR signaling