To make an effective immune response, T cells and B cells must be able to respond to their specific antigen even when it is present at extremely low levels. This is especially important for T cells, as an antigen-presenting cell will display on its surface many different peptides from both self and foreign proteins, and the number of peptide:MHC complexes specific for a particular T-cell receptor is likely to be very low. Some estimates suggest that a naive CD4 T
Fig. 7.10 The B-cell receptor complex is made up of cell-surface immunoglobulin with one each of the invariant signaling proteins Igα and Igβ. The immunoglobulin recognizes and binds antigen but cannot itself generate a signal. it is associated with antigen-nonspecific signaling molecules—igα and igβ. These each have a single iTam (yellow segment) in their cytosolic tails that enables them to signal when the B-cell receptor is ligated with antigen. igα and igβ form a disulfide-linked heterodimer that is non-covalently associated with the heavy chains.
Fig. 7.9 ITAMs recruit signaling proteins that have tandem SH2 domains. The iTams of the T-cell receptor (TcR) and B-cell receptor (BcR) contain tyrosine residues within the motif`…yXX[L/i] X6–9yXX[L/i]…. The spacing between the tyrosines is important in binding to tandem Sh2-containing proteins such as Syk and Zap-70. Left panel: prior to TcR or BcR stimulation, these kinases are in an inactive conformation, known as the autoinhibited conformation. The autoinhibited conformation is stabilized by interactions between the tandem Sh2 domain-kinase domain linker region and the kinase domain that hold the enzyme in a catalytically inactive state. Right panel: after phosphorylation of both tyrosines within one iTam (here depicted as two tyrosines separated by 9-12 amino acids), the tandem Sh2 domains of Syk or Zap-70 can dock cooperatively to both phosphotyrosines, as shown here for Zap-70. By being recruited into the active signaling complex, Zap-70 can itself be phosphorylated, so that it becomes an active kinase that can then phosphorylate its substrates. This final step of Zap-70 activation requires phosphorylation on two tyrosines in the linker region between the tandem Sh2 domains and the kinase domain, together with phosphorylation of a tyrosine in the catalytic site of the kinase domain.
Fig. 7.11 Engagement of co-receptors with the T-cell receptor enhances phosphorylation of the ITAMs. upper panel: for simplicity, we show the cd4 co-receptor engaging the same mhc molecule as the T-cell receptor (TcR), although signaling within receptor microclusters may differ from this arrangement. When T-cell receptors and co-receptors are brought together by binding to peptide:mhc complexes on the surface of an antigen-presenting cell, recruitment of the co-receptor-associated kinase Lck leads to phosphorylation of iTams in cd3γ, δ, and ε, and in the ζ chains. Lower panel: the tyrosine kinase Zap-70 binds to phosphorylated iTams through its Sh2 domains, enabling Zap-70 to be phosphorylated and activated by Lck. Zap-70 then phosphorylates other intracellular signaling molecules.
cell can become activated by fewer than 50 antigenic peptide:MHC complexes displayed by an antigen-presenting cell, and effector CD8 cytotoxic T cells may be even more sensitive. B cells become activated when about 20 B-cell receptors are engaged. These estimates based on in vitro studies may not be precise for cells in vivo, but it is clear that the antigen receptors on T cells and B cells confer remarkable sensitivity to antigen.