Research ArticleNK CELLS

Clonal expansion and compartmentalized maintenance of rhesus macaque NK cell subsets

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Science Immunology  02 Nov 2018:
Vol. 3, Issue 29, eaat9781
DOI: 10.1126/sciimmunol.aat9781

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An enduring NK cell clan

Unlike other immune cells, the processes by which different NK cell subsets expand and are maintained are not well understood. Here, Wu et al. transplanted barcoded hematopoietic progenitor cells into rhesus macaques to follow the production, expansion, and maintenance of NK cells in the peripheral circulation for more than 4 years. They identified oligoclonal CD56CD16+ NK cell populations that segregated into unique clones, expanding or contracting over time and expressing specific surface KIR molecules. Offering a compartmentalized view of NK cell maintenance, distinct mature CD56CD16+ NK cell subpopulations were maintained through self-renewal, independent of differentiation from hematopoietic progenitors or less mature NK cells, even upon challenges representing moderate proliferative stress.

Abstract

Natural killer (NK) cells recognize and eliminate infected and malignant cells. Their life histories are poorly understood, particularly in humans, due to lack of informative models and endogenous clonal markers. Here, we apply transplantation of barcoded rhesus macaque hematopoietic cells to interrogate the landscape of NK cell production, expansion, and life histories at a clonal level long term and after proliferative challenge. We identify oligoclonal populations of rhesus CD56CD16+ NK cells that are characterized by marked expansions and contractions over time yet remained long-term clonally uncoupled from other hematopoietic lineages, including CD56+CD16 NK cells. Individual or groups of CD56CD16+ expanded clones segregated with surface expression of specific killer immunoglobulin-like receptors. These clonally distinct NK cell subpopulation patterns persisted for more than 4 years, including after transient in vivo anti-CD16–mediated depletion and subsequent regeneration. Profound and sustained interleukin-15–mediated depletion was required to generate new oligoclonal CD56CD16+ NK cells. Together, our results indicate that linear NK cell production from multipotent hematopoietic progenitors or less mature CD56+CD16 cells is negligible during homeostasis and moderate proliferative stress. In such settings, peripheral compartmentalized self-renewal can maintain the composition of distinct, differentiated NK cell subpopulations.

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