Full activation of a T-cell requires two different signals. The first, antigen-specific signal, comes when the T-cell receptor recognizes a peptide-MHC complex on the surface of an antigen-presenting cell (APC). This first signal causes events and reactions that can be quantified, such as the expression of the growth factor receptor or IL-2 receptor or the release of certain cytokine molecules. However, full activation of the T-cell requires a second, costimulatory signal involving a different ligand and receptor. Indeed, the antigen-specific signal by itself is a negative regulator of the system and can be used to induce tolerance, as shown in several of the preceding presentations.
At a more complex level, the costimulatory signal appears to be particularly important in activating the CD4 helper cells, which—in either the Th-1 or Th-2 form—plays a critical role in activating other cells of the immune system. And while the signal it transits to the B-lymphocyte may be antigen-nonspecific (e.g., cyryokines such as IL-4), the activation of the helper T-cell is antigen-specific. In this sense, both of the signals received by the B-cell are antigen-specific.
Molecular Signaling in Costimulation. A range of ligands and receptors have been shown to play various roles in costimulatory signals. Perhaps the best-known are the B7 family, which are expressed on the APC in two well-characterized forms, B7.1 and B7.2 (a third form has been proposed). These molecules interact with the CD28 and/or CTLA4 molecules, which are normally expressed on the surface of the responding T-cell. When B7 molecules engage CD28, they turn the T-cell on; when they engage CTLA4, they turn the cell off, thereby providing a feedback loop.
In their resting state, the APC expresses a low level of B7 on its surface, and the T-cell expresses a large amount of the CD28 receptor, and a low but detectable amount of CTLA4. The CTLA4 acts as a buffer, preventing nonspecific activation, because it has about a tenfold-higher affinity for the B7 ligands and, under the limiting conditions of B7, it preferentially occupies these receptors and gives negative signals to the cell. Activation up-regulates B7 on the surface of the APC (first B7.2, later B7.1), rapidly saturating the few CTLA4 receptors on the T-cell and then occupying CD28 molecules, sending positive signals and initiating costimulation. Between 24 and 48 hours later, there is a gradual shift from B7.2 to B7.1 on the APC, inducing an increase in CTLA4 molecules that compete for B7 molecules, send increasing negative signals, and turn off the T-cell—or at least this pathway.
Molecular Response to Costimulation. When CD28 is stimulated in vitro, the predominant effect in tissue culture is a 30- to 100-fold increase in the production of the T-cell growth hormone IL-2, relative to the amount produced