The first intracellular signal generated after the T cell has detected its specific antigen is the phosphorylation of both tyrosines in the ITAMs of the T-cell receptor. This signal is initiated with the help of the CD4 and CD8 co-receptors, which bind to MHC class II molecules and class I molecules, respectively, via their extracellular domains (see Section 4-18), and associate with nonreceptor kinases via their intracellular domains. The Src-family kinase Lck is constitutively associated with the cytoplasmic domains of CD4 and CD8 and is thought to be the kinase primarily responsible for phosphorylation of the ITAMs of the T-cell receptor (see Fig. 7.11). Evidence suggests that binding of the co-receptor to the peptide:MHC complex that binds the T-cell receptor enhances the recruitment of Lck to the engaged T-cell receptor, leading to more efficient phosphorylation of the T-cell receptor ITAMs. The importance of this event is demonstrated by the profound reduction in T-cell development in Lck-deficient mice. This indicates the essential role of Lck in T-cell receptor signaling during the selection of developing T cells in the thymus (discussed in Chapter 8). Lck is important for T-cell receptor signaling in naive T cells and effector T cells, but is less important for the activation or maintenance of memory CD8 T cells by their specific antigen. A related tyrosine kinase, Fyn, is weakly associated with the ITAMs of the T-cell receptor and may have some role in signaling. Whereas mice lacking Fyn develop normal CD4 and CD8 T cells that respond in essentially normal fashion to antigen, mice lacking both Lck and Fyn show a more complete loss of T-cell development than mice lacking Lck alone.
Another role of the co-receptors in T-cell receptor signaling may be to stabilize interactions between the receptor and the peptide:MHC complex. Affinities of individual receptors for their specific peptide:MHC complexes are in the micromolar range, which means that the T-cell receptor:peptide:MHC complexes have half-lives of less than 1 second and dissociate rapidly. The additional binding of a co-receptor to the MHC molecule is thought to stabilize the interaction by increasing its duration, thereby providing time for an intracellular signal to be generated.