Clonal selection of somatic mutations shapes NK cell memory

Abstract Adaptive immune memory relies on selective clonal expansion and persistence of lymphocyte populations. Whether and how clonal selection occurs in innate lymphocytes that lack rearranged antigen receptors remains poorly understood. Here, we used somatic genetics to reconstruct the natural history of human natural killer (NK) cell responses to cytomegalovirus infection. Across a large cohort of healthy seropositive individuals, we found strong clonal dominance in memory NK cells consistent with clonal selection. Dominant memory NK cell clones were marked by coherent receptor and chromatin configurations, emerged early in life and diversified into genetically related subclones. Both an excess of coding mutations, and the reconstructed population dynamics of the dominant clones, provided evidence for positive selection acting on somatic genetic variation. We identified somatic loss-of-function mutations in the chromatin modifier KMT2D , and showed in a mouse model that Kmt2d deletion alters NK-cell fitness depending on timing and environmental context. Together, these findings establish clonal selection as an organizing principle of human NK-cell memory and support a model in which heritable cell states and acquired genetic variation contribute to shape clonal competition.