When a T cell binds to its specific ligand on an antigen-presenting cell, intracellular signaling through the T-cell receptor (TCr) induces a conformational change in LFa-1 that causes it to bind with higher affinity to ICaMs on the antigen-presenting cell. The T cell shown here is a Cd4 T cell.
on resting T cells, the β and γ chains are expressed constitutively. They bind IL-2 with moderate affinity. activation of T cells induces the synthesis of the α chain and the formation of the high-affinity heterotrimeric receptor. The β and γ chains show similarities in amino acid sequence to cell-surface receptors for growth hormone and prolactin, each of which also regulates cell growth and differentiation.
Fig. 9.22 Three kinds of signals are involved in activation of naive T cells by antigen-presenting cells. Binding of the foreign-peptide:self MhC complex by the T-cell receptor and, in this example, a Cd4 co-receptor transmits a signal (arrow 1) to the T cell that antigen has been encountered. effective activation of naive T cells requires a second signal (arrow 2), the co-stimulatory signal, to be delivered by the same antigen-presenting cell (apC). In this example, Cd28 on the T cell encountering B7 molecules on the antigen-presenting cell delivers signal 2, whose net effect is the increased survival and proliferation of the T cell that has received signal 1. ICos and various members of the TnF receptor family may also provide co-stimulatory signals. For Cd4 T cells in particular, different pathways of differentiation produce subsets of effector T cells that carry out different effector responses, depending on the nature of a third signal (arrow 3) delivered by the antigen-presenting cell. Cytokines are commonly, but not exclusively, involved in directing this differentiation.
9-15 Antigen-presenting cells deliver multiple signals for the clonal expansion and differentiation of naive T cells.
When discussing the activation of naive T cells, it is useful to consider at least three different types of signals (Fig. 9.22). The first signal is generated from the interaction of a specific peptide:MHC complex with the T-cell receptor. Engagement of the T-cell receptor with its specific peptide antigen is essential for activating a naive T cell. However, even if the co-receptor—CD4 or CD8—is also ligated, this does not, on its own, stimulate the T cell to fully proliferate and differentiate into effector T cells. Expansion and differentiation of naive T cells involve at least two other kinds of signals: co-stimulatory signals that promote the survival and expansion of the T cells, and cytokines that direct T-cell differentiation into one of the different subsets of effector T cells. Additional signals, such as Notch ligands, can contribute to the effector differentiation of naive T cells, although these signals appear to be of lesser importance than those of lineage-specifying cytokines.
The best-characterized co-stimulatory molecules are the B7 molecules. These homodimeric members of the immunoglobulin superfamily are found exclusively on the surfaces of cells, such as dendritic cells, that stimulate naive T-cell proliferation (see Section 9-8). The receptor for B7 molecules on the T cell is CD28, a member of the immunoglobulin superfamily (see Section 7-21). Ligation of CD28 by B7 molecules is necessary for the optimal clonal expansion of naive T cells; targeted deficiency of B7 molecules or experimental blockade of the binding of B7 molecules to CD28 has been shown to inhibit T-cell responses.
9-16 CD28-dependent co-stimulation of activated T cells induces expression of interleukin-2 and the high-affinity IL-2 receptor.