Natural Killer Cells and Innate Killing of Infected Cells | AI Learning Guide

NK cells decide whether to kill based on a balance of signals. Inhibitory receptors recognize MHC class I, which is normally on healthy cells. Activating receptors recognize stress ligands that appear on infected cells. When MHC class I is present, inhibition dominates and the NK cell is restrained. But many viruses downregulate MHC class I to avoid CD8+ T cells. That loss removes the inhibitory signal, so NK cells kill the infected cell. This is the missing-self hypothesis. NK cells also secrete interferon-gamma, which further activates other immune cells.

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The balance of signals

NK cell activation is determined by the integration of inhibitory and activating signals. Inhibitory receptors recognize MHC class I, which is normally present on healthy cells. Activating receptors recognize stress-induced ligands that appear on infected cells. When MHC class I is present and stress ligands are low, inhibition dominates and the NK cell does not kill. When MHC class I is lost or stress ligands increase, activation dominates and killing occurs.

Missing-self recognition

Because many viruses downregulate MHC class I to evade CD8+ T cells, they become vulnerable to NK cell killing. This creates a trade-off: losing MHC class I helps evade adaptive immunity but triggers innate NK cell attack.

Beyond killing

Activated NK cells also secrete interferon-gamma and chemokines, which enhance macrophage activation and recruit other immune cells, linking innate detection to the broader immune response.