TRIGGERING THE T‐CELL RECEPTOR COMPLEX
Let us now consider a situation in which a T‐cell has encountered a DC displaying the correct peptide–MHC combination and has engaged with the DC such that many of the TCRs on the T‐cell are engaged with a similar number of high‐affinity peptide–MHC molecules on the APC. Such an event will greatly stabilize the interaction between the T‐cell and the DC such that the duration of the encounter (the dwell time) will be sufficient to activate the T‐cell (Figure 7.4). But what is the actual activating event? Put another way, how does the TCR complex register that the switch has been thrown?
Figure 7.4 Interaction between T‐cells and dendritic cells. Scanning electron microscopy analysis of DC–T‐cell interactions within a 3‐D collagen matrix.
Figure 7.6 The CD3 co‐receptor complex. The TCR has no intrinsic signaling activity but signals through the associated CD3 complex. Note that the CD3 complex is thought to comprise one subunit each of CD3γ and δ, two CD3ε subunits, and two disulfide‐linked CD3ζ (zeta) subunits. As depicted in the figure, all of the CD3 co‐receptor subunits contain immunoreceptor tyrosine‐based activation motifs (ITAMs) that can become phosphorylated by kinases activated upon TCR stimulation. Phosphorylation at such motifs creates binding sites for additional signaling molecules that can propagate T‐cell activation signals.
Despite much investigation, we still do not have a clear answer to this question but it appears that both aggregation of the TCR complex, as well as conformational changes within the complex, play key roles in signal initiation. Recall from Chapter 4 that the T‐cell receptor complex is composed of the TCR itself and the CD3 co‐receptor complex. The CD3 co‐receptor complex contains CD3γδεζ, which possess the signaling motifs (ITAMs) necessary for propagation of signals into the cell (Figure 7.6). Recent evidence suggests that in a resting T‐cell the cytoplasmic tails of the CD3ε and CD3ζ molecules are buried in the inner leaflet of the plasma mem brane, which shields their ITAMs from the kinase, called Lck (which we will discuss in the next section), that is needed to get the signal transduction cascade going. Stable MHC–TCR interactions appear to be able to release the CD3ε and CD3ζ tails from the membrane, making them accessible to phospho rylation. As we shall shortly discuss, the signaling cascades that result from TCR stimulation can become quite complex (Figure 7.7); but take it one step at a time and a sense of orderb can be extracted from the apparent chaos.
Figure 7.7 Signaling pathways can become quite complex.