Human Bone Marrow-Derived Myeloid Dendritic Cells Show an Immature Transcriptional and Functional Profile Compared to Their Peripheral Blood Counterparts and Separate from Slan+ Non-Classical Monocytes.

Nathalie Van Leeuwen-Kerkhoff,Tanja D De Gruijl,Theresia M Westers,Arjan A Van De Loosdrecht,Shahram Kordasti,Hetty J Bontkes,Malin Lindstedt,Kristina Lundberg

doi:10.3389/fimmu.2018.01619

Nathalie Van Leeuwen-Kerkhoff, Tanja D De Gruijl + Show 6 more

Open Access

https://doi.org/10.3389/fimmu.2018.01619

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Abstract

The human bone marrow (BM) gives rise to all distinct blood cell lineages, including CD1c+ (cDC2) and CD141+ (cDC1) myeloid dendritic cells (DC) and monocytes. These cell subsets are also present in peripheral blood (PB) and lymphoid tissues. However, the difference between the BM and PB compartment in terms of differentiation state and immunological role of DC is not yet known. The BM may represent both a site for development as well as a possible effector site and so far, little is known in this light with respect to different DC subsets. Using genome-wide transcriptional profiling we found clear differences between the BM and PB compartment and a location-dependent clustering for cDC2 and cDC1 was demonstrated. DC subsets from BM clustered together and separate from the corresponding subsets from PB, which similarly formed a cluster. In BM, a common proliferating and immature differentiating state was observed for the two DC subsets, whereas DC from the PB showed a more immune-activated mature profile. In contrast, BM-derived slan+ non-classical monocytes were closely related to their PB counterparts and not to DC subsets, implying a homogenous prolife irrespective of anatomical localization. Additional functional tests confirmed these transcriptional findings. DC-like functions were prominently exhibited by PB DC. They surpassed BM DC in maturation capacity, cytokine production, and induction of CD4+ and CD8+ T cell proliferation. This first study on myeloid DC in healthy human BM offers new information on steady state DC biology and could potentially serve as a starting point for further research on these immune cells in healthy conditions as well as in diseases.

Highlights

The human bone marrow (BM) compartment is the main site of hematopoiesis
Dendritic cell and monocyte subsets were enumerated in the mononuclear cell fraction of fresh peripheral blood (PB) (n = 17–21) and BM (n = 13–20) samples from non-paired healthy donors (HD)
Cell populations were characterized by the expression of the cell-identifying markers CD1c and CD141 for the myeloid dendritic cell (DC) subsets. cDC2 were further defined as CD19−/CD14− and HLA-DR+/CD11c+

Summary

Introduction

The human bone marrow (BM) compartment is the main site of hematopoiesis It harbors early progenitor cells as well as more differentiated cells that will enter the circulation in a later stage for homing to secondary lymphoid organs or effector sites to mediate their immune functions. Increasing knowledge on the sequential development of common and early progenitors to committed and more differentiated precursors may support the understanding of normal and aberrant hematopoiesis. This is for instance exemplified by selective cell lineage depletion in primary immunodeficiencies such as seen in patients with GATA2 mutations [24,25,26]. Published data support the fact that these circulating precursors are less mature and differentiated than their counterparts in peripheral tissues [15, 24, 28]

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