Acquired somatic mutations in PNH reveal long-term maintenance of adaptive NK cells independent of HSPCs

Marcus A. F. Corat, Heinrich Schlums, Chuanfeng Wu, Jakob Theorell, Diego A. Espinoza, Stephanie E. Sellers, Danielle M. Townsley, Neal S. Young, Yenan T. Bryceson, Cynthia E. Dunbar and Thomas Winkler

Key Points

  • GPIposCD56dim NK cells with an adaptive phenotype persist long-term in PNH patients.

  • Clonal tracking of adaptive NK cells in PNH patients suggests maintenance independent of HSPCs.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.


Natural killer (NK) cells have long been considered short-lived effectors of innate immunity. However, recent animal models and human studies suggest that subsets of NK cells have adaptive features. We investigate clonal relationships of various NK-cell subsets, including the adaptive population, by taking advantage of naturally occurring X-linked somatic PIGA mutations in hematopoietic stem and progenitor cells (HSPCs) from patients with paroxysmal nocturnal hemoglobinuria (PNH). The affected HSPCs and their progeny lack expression of glycosylphosphatidylinositol (GPI) anchors on their cell surface, allowing quantification of PIGA-mutant (GPI-negative) HSPC-derived peripheral blood cell populations. The fraction of GPI-negative cells within the CD56dim NK cells was markedly lower than that of neutrophils and the CD56bright NK-cell compartments. This discrepancy was most prominent within the adaptive CD56dim NK-cell population lacking PLZF expression. The functional properties of these adaptive NK cells were similar in PNH patients and healthy individuals. Our findings support the existence of a long-lived, adaptive NK-cell population maintained independently from GPIposCD56dim.

  • Submitted August 17, 2016.
  • Accepted November 4, 2016.
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