Figure 3.

SCHOOL model of T-cell receptor signaling. A schematic representation of the SCHOOL-based molecular mechanisms of T-cell receptor (TCR) signaling. Immunoreceptor tyrosine-based activation motifs (ITAMs) are shown as gray rectangles. TCR-CD3-ζ components are represented as whole polypeptides and as a simplified axial view. All interchain interactions in intermediate complexes are shown by dotted arrows reflecting their transition state. Circular arrow indicates ligand-induced receptor reorientation. Interaction with multivalent ligand (not shown) clusters the receptors and pushes them to reorientate (I) and bring signaling subunits into a correct relative orientation and in sufficient proximity in the formed receptor oligomer (for illustrative purposes, receptor dimer is shown), thus starting the trans-homointeractions between ζ molecules (II). Then, two alternative pathways can take a place depending on the nature of activating stimuli. First is going through a stage IV resulting in formation of ζ2 dimer (dimer of dimers) and phosphorylation of the ζ ITAM tyrosines, thus triggering downstream signaling events. Then, the signaling ζ oligomers formed subsequently dissociate from the TCR-CD3 complex, resulting in internalization of the remaining engaged TCR-CD3 complexes (VII). This pathway leads to partial (or incomplete) T cell activation. Alternatively, the intermediate complex formed at the stage II can undergo further rearrangements, starting trans-homointeractions between CD3 proteins (III) and resulting in formation of an oligomeric intermediate. Again, the stages I, II and III can be reversible or irreversible depending on interreceptor proximity and relative orientation of the receptors in TCR dimers/oligomers as well as on time duration of the TCR-ligand contact and lifetime of the receptor in TCR dimers/oligomers that generally correlate with the nature of the stimulus and its specificity and affinity/avidity. Next, in the signaling oligomers formed (III), the ITAM tyrosines undergo phosphorylation by PTKs that leads to generation of the activation signal, dissociation of signaling oligomers and internalization of the remaining engaged TCRαβ chains (VIII, XI). This pathway provides at least two different activation signals from the ζ and CD3 signaling oligomers (signals A and B), respectively, and results in full T-cell activation. The distinct signaling through ζ and CD3 oligomers (or through various combinations of signaling chains in CD3 oligomeric structures) might be also responsible for distinct functions such as T-cell proliferation, effector functions, T-cell survival, pathogen clearance, TCR anergy, etc. In addition, the signaling oligomers formed can sequentially interact with the signaling subunits of nonengaged TCRs resulting in formation of higher-order signaling oligomers, thus amplifying and propagating the activation signal (not shown). Also, this leads to the release and subsequent internalization of the remaining nonengaged TCR complexes and/or TCRαβ chains (not shown). Abbreviations: PTK, protein tyrosine kinase. Phosphate groups are shown as filled gray circles.