CD8+ cytotoxic T cells read viral peptides on MHC class I. Removing MHC class I from the surface hides the infected cell from that surveillance, but it also removes the inhibitory signal that MHC class I delivers to NK cells through inhibitory receptors such as KIR and NKG2A. Loss of MHC class I therefore shifts the NK cell toward activation, because activating ligands on the stressed cell are no longer balanced by inhibition. The trade-off is real, and viruses solve it in two ways: they retain a single MHC class I allele that carries the inhibitory signal while discarding the others, or they express a viral MHC class I homolog that engages NK inhibitory receptors directly. Human cytomegalovirus uses both approaches, and the result is a cell that is invisible to CD8+ T cells but still sends the NK cell a stand-down signal.
Learn MotionHow Viruses Enter Cells, Replicate, and Evade Immunity
Immune Evasion Strategies
Hiding from T Cells Without Waking NK Cells
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Look at the infected cell in the center. On the left, the normal cell displays MHC class I, which does two jobs: it shows viral peptide to the CD8+ T cell, and it engages the NK cell's inhibitory receptor. Now follow the middle panel. The virus has removed MHC class I. The CD8+ T cell loses its target, but the NK cell loses its inhibitory signal, so the balance tips toward killing. The right panel shows how the virus resolves that: it keeps one MHC class I allele, or expresses a viral MHC homolog, so the inhibitory receptor is still engaged while the peptide display that the T cell needs is gone. The cell is invisible to T cells but still tells the NK cell to stand down.
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