We are excited to share our recent paper with the title “Clonal expansion and epigenetic inheritance shape long-lasting NK cell memory”, led by @TimoRckert, in which we study the origin and maintenance of human adaptive NK cells! nature.com/articles/s41590-0…
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Open chromatin of adaptive NK showed selective enrichment of AP1 motifs, recently established as a sign of inflamm. memory by Elaine Fuchs' lab (incl. in Ly49H+ NK post-MCMV by @SunLab_Official) which defines the convergent memory signature shared by all adaptive NK ex vivo.
Oct 26, 2022 · 3:39 PM UTC
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How does HCMV infection induce this memory state? ASAP-seq after peptide-stimulation via NKG2C and/or pro-inflammatory cytokines revealed a synergistic role of these signals for AP1 activity, resulting in global remodeling that recapitulated the ex vivo signature of adaptive NK.
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Besides this global convergent signature, the chromatin landscape in individual donors showed a remarkable degree of adaptive NK heterogeneity, distinguishing several subclusters by hundreds of open chromatin regions. What could these peaks unique to each subcluster signify?
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We hypothesized that this could be due to a founder effect during adaptive NK expansion and made two testable predictions:
1) A founder effect should result in reduced heterogeneity. Indeed, cells in each adaptive subcluster were more similar to each other than convent. CD56dim.
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2) To be detectable on the population level, NKG2C+ founder NK would have to undergo drastic clonal expansion and be maintained in their unique epigenetic states. Utilizing the recent mitochondrial lineage tracing method of @LeifLudwig & @CalebLareau... doi.org/10.1038/s41587-020-0…
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...we found a specific association of clonotypes flagged by a single mitochondrial mutation to adaptive subclusters defined by their epigenetic states. Chromatin specifically open in individual clonotypes contributed to the epigenetic repertoire of the adaptive NK compartment.
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Finally, we demonstrated the stability of adaptive NK clonotypes in their unique epigenetic states by following donors up to 19 months in time.
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Altogether, we reveal drastic and stably maintained clonal expansion of adaptive NK in HCMV+ individuals. Clones show a convergent inflammatory memory signature, superimposed on a private set of clonally inherited open chromatin regions, shaping NK epigenetic memory repertoire.
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