Each checkpoint in the activation pathway can be removed or weakened, and the consequence follows directly from what that checkpoint normally does. Removing costimulation by blocking CD28 or its ligands prevents activation and produces anergy. Removing suppression by depleting regulatory T cells allows self-reactive conventional T cells to activate against self-antigen. Removing inhibitory receptor function by blocking CTLA-4 or PD-1 lowers the threshold for activation and increases the likelihood of an exaggerated response. In each case, the effect on the likelihood of overreaction is predictable from the checkpoint's normal role. This is the central claim of the chapter: overreaction is not a random failure but the expected outcome of a specific checkpoint being lost.
Learn MotionWhen the Immune System Turns on the Body: Mechanisms of Overreaction
The Logic of Immune Activation: Why Restraint Is the Default
Removing a Checkpoint: Predicting the Consequence
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Toggle each checkpoint off one at a time and watch the predicted likelihood of overreaction change. Turning off costimulation prevents activation, so the risk drops. Turning off regulatory T cell suppression allows self-reactive cells to activate, so the risk rises. Turning off inhibitory receptors lowers the activation threshold, so the risk rises further. The pattern is consistent: the effect of losing a checkpoint is determined by what that checkpoint normally does. Overreaction is the predictable consequence of a specific loss, not a random event.
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