CD56bright Human NK Cells Differentiate into CD56dim Cells: Role of Contact with Peripheral Fibroblasts

Abstract

Human NK cells are divided into CD56brightCD16− cells and CD56dimCD16+ cells. We tested the hypothesis that CD56bright NK cells can differentiate into CD56dim cells by prospectively isolating and culturing each NK subset in vitro and in vivo. Our results show that CD56bright cells can differentiate into CD56dim both in vitro, in the presence of synovial fibroblasts, and in vivo, upon transfer into NOD-SCID mice. In vitro, this differentiation was inhibited by fibroblast growth factor receptor-1 Ab, demonstrating a role of the CD56 and fibroblast growth factor receptor-1 interaction in this process. Differentiated CD56dim cells had reduced IFN-γ production but increased perforin expression and cytolysis of cell line K562 targets. Flow cytometric fluorescent in situ hybridization demonstrated that CD56bright NK cells had longer telomere length compared with CD56dim NK cells, implying the former are less mature. Our data support a linear differentiation model of human NK development in which immature CD56bright NK cells can differentiate into CD56dim cells.

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

“…During maturation, pre-NK cells and iNK express high levels of CD56 [18,19]. Furthermore, CD56 bright from SLO as well as from peripheral blood may acquire many features of CD56 dim after stimulation with cytokines [5,12,20,21]. These observations have introduced the notion that CD56 bright are immature and somewhat obscured the definitions of iNK, ''less mature'' NK cells, cytokine-producing CD56 bright and ''precursors of CD56 dim ''.…”

“…CD56 bright isolated from peripheral blood start to express KIR and CD16, downregulate c-kit and acquire cytolytic activity upon activation by IL-2 or IL-15 [5,12]. However, IL-15 induces only CD56 dim -like levels of CD56, CD16 and KIR in CD56 bright in contact with fibroblasts [20] or after infusion of CD56 bright into immune-deficient mice [20,21]. Furthermore, skewing NK-cell differentiation toward CD56 dim is far superior when IL-15 is trans-presented by IL-15Ra-Fc [21], which mimics the way IL-15 is presented by dendritic cells to NK cells in lymph nodes [22].…”

Education of hyporesponsive NK cells by cytokines

“…Nonetheless, when KIR3DL1 1 NK cells were re-sorted in order to minimize the bias of KIR À cell overgrowth, most NK cells maintained KIR expression, similar to ex vivo KIR3DL1 1 ones. Several groups have employed murine stromal cells [10] or human fibroblasts [13] and the addition of cytokines to induce KIR acquisition by NK cells. In our system cytokines alone in the absence of any accessory cells were able to induce KIR expression, but that was restricted to a small subset of NK cells.…”

“…Since KIR 1 cells proliferate much less than KIR À ones [9,10], NK cells that acquired KIR expression were almost lost after 4 wk of culture. This finding might explain why KIR induction by cytokines has been underestimated [10,13]. Nonetheless, when KIR3DL1 1 NK cells were re-sorted in order to minimize the bias of KIR À cell overgrowth, most NK cells maintained KIR expression, similar to ex vivo KIR3DL1 1 ones.…”

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…As murine NK cells do not express CD56, RAG2 −/− γ c −/− mice transplanted with human haematopoietic stem cells have been used to show that CD56 bright NK cells differentiated linearly into CD56 dim NK cells, acquiring CD16 and KIR expression 65, 66. This has also been shown in vitro by culturing CD56 bright NK cells in the presence of synovial or skin fibroblasts, or cytokines 52, 67…”