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exchange factors like SOS and VAB as well as GTG-ase activity and another pathway activated by protein kinase C (PKC). As researchers zero in on these molecular mechanisms, they will eventually have a full understanding of this process.

At bottom, then, anergy can be characterized as negative regulation induced by T-cell receptor occupancy in the absence of costimulation. Signal 1 alone actually induces an inhibitor that operates on the ras pathway, blocking ras activation. Because this happens at the same time that the signals activating the IL-2 gene, the initial response is to produce IL-2. But the inhibitor persists after the initial response dies down, and when the cell is restimulated it behaves like a negative feedback loop, preventing subsequent activation.

When signals 1 and 2 are both received, on the other hand, there is a far greater production of IL-2, followed by proliferation of the cell. At first researchers thought that cell division alone was enough to dilute out the inhibitor; it now appears that signal transduction through the IL-2 receptor, particularly the gamma chain, can antagonize the induction of anergy, presumably by inhibiting the production of the inhibitor. The biochemical basis of this mechanism has not yet been worked out. In this case, it would appear that costimulation antagonizes the anergic effect in two ways: (1) by augmenting IL-2 production, and (2) by inhibiting inhibitor production.

Finally, recent studies have demonstrated that, even in the presence of normal costimulation, it is possible to modify the peptides in certain MHC complexes by making certain amino acid substitutions that probably decrease the affinity of interaction with the TCR. These so-called “partial agonists” are also capable of inducing anergy, apparently by interfering with the transduction of signal 1 and preventing the downstream event, namely the production of IL-2. This result demonstrates that it is possible to achieve anergy through two different biochemical mechanisms—lack of costimulation, and partial signal transduction.

T-Cell Receptors and Apoptosis. Programmed cell death was described above. However, the resting T-cell has on its surface the CD95 molecule, which is fas. When the cell is activated through antigen stimulation and costimulation, one result is the production of additional fas ligands on the surface. These ligands form a trimeric complex that can interact with the receptor on the same cell, or those on other cells. Researchers hypothesize that this interaction may be what signals the cell to undergo apoptosis. This would explain why interfering with the CD28 system had no effect on apoptosis.

Another team of researchers investigated the roles of antigen-specific and costimulatory receptors by looking at T-cells stimulated with anti-CD3 and measuring the effect of anti-CD28, as reflected in the production of Bcl-2 family members, which are important in protecting the cell against apoptosis. They found that the combination of the two signals resulted in very high levels of Bcl-x. In this case, the antagonist to CD28 was solubilized CTLA4 receptor (with its greater affinity for B7) that has been fused with immunoglobulin for stability. In



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