T Cells Require Two Types of Signals for Full Activation
All T cells require a signal via their TCR for activation, but that signal is not sufficient: the T cell also needs co-stimulatory signals. To perceive these co-stimulatory signals, T cells carry on their surface several additional receptors, of which the CD28 molecule is the best-known example. CD28 interacts with CD80 and CD86, two surface glycoproteins on the professional APCs with which the T cell interacts. Expression of CD80 and CD86 increases when these APCs have themselves received the proper stimulatory signals, for example, by engagement of their Toll-like receptors (TLRs). The signals delivered to T cells via CD28 synergize with signals that emanate from the TCR when bound to its cognate self-MHC–peptide antigen complex, all of which are required for full T-cell activation (Figure 23-33).
FIGURE 23-33 Signals involved in T-cell activation and its termination. The two-signal model of T-cell activation involves recognition of an MHC-peptide complex by the T-cell receptor, which constitutes signal 1 (step 1), along with recognition of co-stimulatory molecules (CD80, CD86) on the surface of an antigen-presenting cell, which constitutes signal 2 (step 2). If co-stimulation is not provided, the newly engaged T cell becomes unresponsive (anergic). The provision of both signal 1 via the T-cell receptor and signal 2 via engagement of CD80 and CD86 by CD28 allows full activation. Full activation, in turn, leads to increased expression of CTLA4 (step 3). After moving to the T-cell surface, CTLA4 binds CD80 and CD86, leading to inhibition of the T-cell response (step 4). Because the affinity of CTLA4 for CD80 and CD86 is greater than that of CD28, T-cell activation is eventually terminated.
T cells, once activated, also express receptors that provide an attenuating or inhibitory signal upon recognition of these very same co-stimulatory molecules, providing negative feedback regulation. The CTLA4 protein, whose expression in T cells is induced only upon activation, competes with CD28 for binding of CD80 and CD86. Because the affinity of CTLA4 for the CD80 and C86 proteins is higher than that of CD28, the inhibitory signals provided through CTLA4 will ultimately overwhelm the stimulatory signals coming via CD28. Co-stimulatory molecules can thus be stimulatory or—as was discovered later without adjusting the nomenclature—inhibitory, and they therefore provide an important means of controlling the activation status and duration of a T-cell response.