Somatic genetic variation shapes clonal selection of memory NK cells

Dominant memory natural killer cell clones in cytomegalovirus-seropositive humans show strong clonal dominance, with coherent receptor and chromatin configurations emerging early and diversifying into related subclones.

• Why it matters: Clonal selection in innate lymphocytes without rearranged antigen receptors is unclear, limiting understanding of how NK-cell memory is organized and persists.
• What they did: Using somatic genetics to reconstruct human NK-cell response natural history across a large cohort of healthy seropositive individuals, the study combined coding-mutation excess with reconstructed dominant-clone dynamics to test for positive selection.
• The result: Somatic loss-of-function mutations in the chromatin modifier KMT2D were identified, and in a mouse model Kmt2d deletion altered NK-cell fitness depending on timing and environmental context, supporting clonal selection in NK-cell memory.

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