T-cell virtuosity in ''knowing thyself"

Abstract

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.

Keywords: T cell; T cell antigen receptor (TCR); TCR signalling; allosteric activation; antigen recognition.

Figure 1

A hypothetical unifying model for TCR-CD3 activation leading to T-cell activation. The series of events depicted here is a summary of the process described in the paper, omitting for simplicity molecular details. The model contemplates a temporal cascade that initiates with an allosterically regulated-activation of the inactive TCR-CD3 (inactive Receptor (R_i) induced simply by peptide-MHC (L) binding, leading to very fast (< 1 ms) tyrosine (Y) exposure in R_a to active-Lck (Lck_A). Lck_A and SHP-1 negotiate ITAM phosphorylation (pY-ITAMs), eventually leading to 2pY-ITAMs if receptor occupancy is adequate and R_a can now bind and activate ZAP-70 to connect to the LAT protein scaffold for signal diversification (59). Data discussed in the text suggest that all sequelae of events take 10 s or so after ligand binding. The proposed model considers that only R_a can form tight clusters, while ZAP-70 (not shown) remains dynamically bound to R_a. For simplicity, co-receptors have been omitted but if they are required for weak ligands, at a certain point they might depart from clustered R_as. Other events should further stabilise the signal perhaps by condensation of signalling effectors near clustered R_as. It is in the next few hours that key cell decisions will be made that involve nuclear events necessary for cell cycle entry and differentiation.

Figure 2

Molecular dynamic simulation of the entire TCR-CD3 complex (Courtesy of Dr Dheeraj Prakaash). The simulation of the full TCR-CD3 complex, including the CD3 intracellular tails, was for a total of five times for five µs and carried out according to the conditions described in (101). The lipid bilayer was composed of seven different lipids (including cholesterol and PIPs) and it is depicted as a grey band. Three snapshots are shown. (A) upper and lower panels are TCR-CD3 side and bottom (cytosol) views, respectively. Note the changes in the configurations of ectodomains, TMDs, and intracellular tails, indicate that TCR-CD3 is a relatively flexible complex with great potential for allosterically-regulated activation. Of interest is also the potential for correlated movements of these three TCR-CD3 domains perhaps exploited for the propagation of allosterically-driven changes in the three isoforms shown (“closed”, semi-open, fully-open). (B) TCR-CD3 side of two snapshots emphasising two extreme configurations one “open” (left) and the other “closed” (right). In the simulations, the transition from open to closed takes two-three hundred ns.