‘Emergency exit’ of bone-marrow-resident CD34+DNAM-1brightCXCR4+-committed lymphoid precursors during chronic infection and inflammation

Abstract

During chronic inflammatory disorders, a persistent natural killer (NK) cell derangement is observed. While increased cell turnover is expected, little is known about whether and how NK-cell homeostatic balance is maintained. Here, flow cytometric analysis of peripheral blood mononuclear cells in chronic inflammatory disorders, both infectious and non-infectious, reveals the presence of a CD34+CD226(DNAM-1)brightCXCR4+ cell population displaying transcriptional signatures typical of common lymphocyte precursors and giving rise to NK-cell progenies with high expression of activating receptors and mature function and even to α/β T lymphocytes. CD34+CD226brightCXCR4+ cells reside in bone marrow, hardly circulate in healthy donors and are absent in cord blood. Their proportion correlates with the degree of inflammation, reflecting lymphoid cell turnover/reconstitution during chronic inflammation. These findings provide insight on intermediate stages of NK-cell development, a view of emergency recruitment of cell precursors, and upgrade our understanding and monitoring of chronic inflammatory conditions.

The Broad Spectrum of Human Natural Killer Cell Diversity

“…This could occur in response to extrinsic local factors such as transforming growth factor-beta (TGF-β) that has been shown to promote trNK phenotypes in human uterus and mouse salivary gland tissues (Cortez et al, 2016; Keskin et al, 2007). Alternative possibilities are that trNK cells derive through completely distinct developmental pathways, potentially starting from distinct tissue-resident HPC populations or NK cell progenitor populations that have been described (Bozzano et al, 2015; Renoux et al, 2015). In addition, trNK cells may be produced via “tissue-imprinting” (e.g.…”

Hematopoietic Stem/Progenitor Cells and the Pathogenesis of HIV/AIDS

“…Importantly, HSPCs require inflammatory signals in their development (Luis et al, 2016), and therefore may contribute to inflammation (Fischer and Agrawal, 2013). A recent study reported the emergence of a CD34 + CD226(DNAM-1) bright CXCR4 + LP subset in association with chronic HIV infection and inflammation, reflecting altered dynamics of natural killer (NK) cells and α/β T cells (Bozzano et al, 2015; Figure 1). Finally, there has recently been an emerging trend to interpret some hematopoietic changes during the course of HIV infection as the accelerated senescence of HSPCs (Appay and Sauce, 2017;Fali et al, 2018;Fastenackels et al, 2019).…”

Understanding the Synergy of NKp46 and Co-Activating Signals in Various NK Cell Subpopulations: Paving the Way for More Successful NK-Cell-Based Immunotherapy

“…Moreover, CD56 bright and CD56 dim NK cell subsets show substantially different activation pathways (CD56 bright by cytokines, CD56 dim by targets), respond differently to cytokine stimulation and exhibit distinct chemokine-driven tissue distribution and trafficking profiles [14,20,[22][23][24]. To this regard, it has been recently characterized a novel CD34 + DNAM-1 bright CXCR4 + NK precursor that gives rise to mature "licensed" NK cells, further suggesting the possibility of concomitant NK cell development from different CD34 + progenitors [21]. Indeed, using different chemokine/cytokine receptor expression and different end-organ trafficking [20,21,[74][75][76][77], we can draw an association between CD56 dim NK cells and CD34 + DNAM-1 bright CXCR4 + (CD117 neg ) NK precursors (both preferentially expressing CX3CR1 and CXCR1), while CD56 bright NK cells can be associated to CD34 + DNAM-1 neg NK progenitors (both preferentially expressing CD62L and CD117 + ).…”

“…To this regard, it has been recently characterized a novel CD34 + DNAM-1 bright CXCR4 + NK precursor that gives rise to mature "licensed" NK cells, further suggesting the possibility of concomitant NK cell development from different CD34 + progenitors [21]. Indeed, using different chemokine/cytokine receptor expression and different end-organ trafficking [20,21,[74][75][76][77], we can draw an association between CD56 dim NK cells and CD34 + DNAM-1 bright CXCR4 + (CD117 neg ) NK precursors (both preferentially expressing CX3CR1 and CXCR1), while CD56 bright NK cells can be associated to CD34 + DNAM-1 neg NK progenitors (both preferentially expressing CD62L and CD117 + ). CD117 antigen (c-kit receptor) had been already indicated as an exclusive marker of CD56 bright NK cell subset [78] and proved to be one of the best way to detect CD56 bright NK cells and to distinguish them from CD56 dim NK cells when they are developed in vitro from PB CD34 + hematopoietic progenitors [17].…”

“…CD56 bright and CD56 dim NK cells have been proposed to represent either NK cells at different stages of differentiation or different NK cell subpopulations [12,13,16,17]. Consistent with this latter hypothesis, there is evidence of their preferential responses to distinct types of stimuli (target-vs. cytokine-mediated activation), of their differentiation from distinct hematopoietic progenitors and of their distinct chemokine driven tissue distribution and trafficking profiles [14,[17][18][19][20][21]. As a matter of fact, CD56 dim NK cells are preferentially activated after target cell recognition, whereas CD56 bright NK cells by NK cell-activating cytokines.…”