For a peptide:MHC complex to activate T cells, it must bind directly to the T-cell receptor (Fig. 7.11, upper panel, and see Fig. 4.22). However, it remains unclear precisely how this extracellular recognition event is transmitted across the T-cell membrane to initiate signaling. Questions remain as to the stoichiometry and physical arrangement of T-cell receptors and peptide:MHC complexes required to initiate the signaling cascade. We will discuss this area of active research only briefly before moving on to explain well-understood intracellular events that occur after antigen recognition.
One suggestion is that signaling is initiated by T-cell receptor dimerization through formation of ‘pseudo-dimeric’ peptide:MHC complexes containing one antigen peptide:MHC molecule and one self peptide:MHC molecule on the surface of the antigen-presenting cell. This model relies on a weak interaction occurring between the T-cell receptor and self peptide:MHC complexes, stabilized by the CD4 or CD8 co-receptor interactions with the self peptide:MHC complexes, but it would explain signaling induced by low densities of antigenic peptides. An additional possibility is that the antigenic peptide:MHC complex induces a conformational change in the T-cell receptor, or its associated CD3 and ζ chains, that promotes receptor phosphorylation; however, direct structural evidence supporting this model is still lacking.
It has also been suggested that signaling might involve receptor oligomerization, or clustering, as antibodies that bind to and cross-link T-cell receptors can activate T cells. Since antigenic peptides are vastly outnumbered by other peptides displayed on the surface of the antigen-presenting cell, it is unlikely that physiologic amounts of antigen induce conventional oligomerization as observed with antibodies. However, assemblies of small numbers of T-cell receptors called microclusters have been observed in the zone of contact between the T cell and the antigen-presenting cell. These microclusters form rapidly following TCR stimulation, and quickly merge with microclusters containing downstream signaling components, such as scaffolds and adaptors. Current evidence indicates that signaling is initiated in these microclusters. One popular model proposes that signal initiation takes place when inhibitory signaling proteins are excluded from these complexes. A key component of this model is that prior to TCR signaling, activating and inhibitory enzymes are in a balanced equilibrium; the initiation of signaling occurs when this equilibrium is perturbed in favor of the activating modifications.
7-9 Antigen recognition by the T-cell receptor and its co-receptors leads to phosphorylation of ITAMs by Src-family kinases, generating the first intracellular signal in a signaling cascade.