Evidence for discrete stages of human natural killer cell differentiation in vivo

Abstract

Human natural killer (NK) cells originate from CD34(+) hematopoietic progenitor cells, but the discrete stages of NK cell differentiation in vivo have not been elucidated. We identify and functionally characterize, from human lymph nodes and tonsils, four NK cell developmental intermediates spanning the continuum of differentiation from a CD34(+) NK cell progenitor to a functionally mature NK cell. Analyses of each intermediate stage for CD34, CD117, and CD94 cell surface expression, lineage differentiation potentials, capacity for cytokine production and natural cytotoxicity, and ETS-1, GATA-3, and T-BET expression provide evidence for a new model of human NK cell differentiation in secondary lymphoid tissues.

CD56bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

“…The combination of CD11b and the TNF-receptor family member CD27 allows a further discrimination of NK-cell maturation stages. CD11b low iNK cells first express CD27 and then differentiate through a CD11b 1 CD27 1 to a CD11b 1 CD27 À stage that is considered to be the most mature [13,14,19,35]. We found that all ptCD56 bright express CD11b at the same high level as normal CD56 bright (for a representative example, see Fig.…”

“…Although some of the NK cells in SLO might be CD56 bright recirculating from the blood, others could represent early maturation stages of NK cells developing from hematopoietic precursor cells that repopulate extramedullary tissues and retain multi-lineage reconstitution capacity [16]. Caligiuri's group has identified lymphocytes in tonsils and lymph nodes representative of distinct stages of NK-cell development that differentiated into NK cells expressing high levels of CD56 [17][18][19]. NK-cell lineage commitment occurred in cells referred to as immature NK cells (iNK) that expressed no, or only very low levels of the NK-cell-associated markers NKp46, CD94, KIR and CD16.…”

“…Mature NK cells cultured in the presence of cytokines express markers such as HLA-DR [8] and NKp44 [23] that were downregulated during progression of pre-NK cells to more mature developmental stages [19]. Furthermore, CD56 dim upregulate CD56 after activation by cytokines [24], downregulate CD16 after contact with target cells [25] and acquire receptors to home to lymph nodes after stimulation with IL-18 [26].…”

“…4, lower panel). The latter is another strong indication that ptCD56 bright are in vivo cytokine-activated CD56 bright rather than immature precursors.Impact of addition or withdrawal of cytokines on CCR7, c-kit and CD127 expression by CD56 bright , ptCD56 bright and NK CCR7, c-kit and CD127 are markers used to define distinct NKcell lineages [37,38] or different NK-cell subsets [4,9,12,15,17,19]. Approximately, half of the CD56 bright in normal peripheral blood are CCR7 1 , whereas virtually all ptCD56 bright are negative (Fig.…”

Mouse fetal and embryonic liver cells differentiate human umbilical cord blood progenitors into CD56-negative natural killer cell precursors in the absence of interleukin-15

“…Although NK cells derive from marrow derived CD34 + cells [6,30], recent data support a role for differentiation in peripheral lymph nodes [46,47]. Although we and others have used the mouse feeder AFT024 to induce NK cell differentiation from CD34 + progenitors [25,48], here we show that EL08-1D2, another mouse microenvironment, is significantly better at recapitulating NK cell development.…”