A Human CD34(+) Subset Resides in Lymph Nodes and Differentiates into CD56brightNatural Killer Cells

Abstract

In humans, T cells differentiate in thymus and B cells develop in bone marrow (BM), but the natural killer (NK) precursor cell(s) and site(s) of NK development are unclear. The CD56bright NK subset predominates in lymph nodes (LN) and produces abundant cytokines compared to the cytolytic CD56dim NK cell that predominates in blood. Here, we identify a novel CD34dimCD45RA(+) hematopoietic precursor cell (HPC) that is integrin alpha4beta7bright. CD34dimCD45RA(+)beta7bright HPCs constitute <1% of BM CD34(+) HPCs and approximately 6% of blood CD34(+) HPCs, but >95% of LN CD34(+) HPCs. They reside in the parafollicular T cell regions of LN with CD56bright NK cells, and when stimulated by IL-15, IL-2, or activated LN T cells, they become CD56bright NK cells. The data identify a new NK precursor and support a model of human NK development in which BM-derived CD34dimCD45RA(+)beta7bright HPCs reside in LN where endogenous cytokines drive their differentiation to CD56bright NK cells in vivo.

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

“…They do show, however, that the level of expression of c-kit and CD127, two receptors often used as markers to define distinct NK-cell lineages [37,38] or different NK-cell subsets [4,9,12,15,17,19] may simply reflect the cytokine level of the environment they have been isolated from and that caution should be taken to interpret low c-kit-or CD127-levels as proof of maturation of CD56 bright toward CD56 dim .…”

“…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.…”

“…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.…”

Germ‐line and rearranged Tcrd transcription distinguish bona fide NK cells and NK‐like γδ T cells

“…Therefore the thymus is not essential for development of CD127 + NK cells. As has been suggested for the CD56 bright population of human NK cells, which are also CD127 + , selective development of CD127 + NK cells may occur in other organs such as the lymph nodes [40]. Alternatively, the non-uniform representation of CD127 + NK cells in different organs may be due to other mechanisms connected to homeostatic regulation by IL-7.…”

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.…”