Clave, E. | Search bioRxiv

bioRxiv2024

Generation of natural killer and myeloid cells in a 3D artificial marrow organoid system

The human bone marrow (BM) microenvironment involves hematopoietic and non-hematopoietic cell subsets organized in a complex architecture. Tremendous efforts have been made to model it in order to analyse normal or pathological hematopoiesis and its stromal counterpart. Herein, we report an original, fully-human in vitro 3D model of the BM microenvironment dedicated to study interactions taking place between mesenchymal stromal cells (MSC) and hematopoietic stem and progenitor cells (HSPC) during the hematopoietic differentiation. This artificial marrow organoid (AMO) model is highly efficient to support NK cell development from the CD34+ HSPC to the terminally differentiated NKG2A-KIR2D+CD57+ NK subset. In addition, myeloid differentiation can also be recapitulated in this model. Moreover, mature NK cell phenotype showed significant differences in the AMO compared to a conventional 2D coculture model for the expression of adhesion molecules and immune checkpoint receptors, thus better reflecting the NK cell behaviour in the BM microenvironment. Lastly, we proved that our model is suitable for evaluating anti-leukemic NK cell function in presence of treatments. Overall, the AMO is a versatile, low cost and simple model able to efficiently recapitulate hematopoiesis and granting better drug response taking into account both immune and non-immune BM microenvironment interactions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=187 HEIGHT=200 SRC="FIGDIR/small/575527v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@f9288corg.highwire.dtl.DTLVardef@1d51c8corg.highwire.dtl.DTLVardef@4563a9org.highwire.dtl.DTLVardef@1920e3c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2020

Altered basal lipid metabolism underlies the functional impairment of naive CD8+ T cells in elderly humans

BackgroundAging is associated with functional deficits in the naive T cell compartment, which compromise the generation of de novo immune responses against previously unencountered antigens. The mechanisms that underlie this phenomenon have nonetheless remained unclear. MethodsBiochemical and functional properties of naive CD8+ T cells were characterized and compared between middle aged and older individuals. FindingsWe identified an age-related link between altered basal lipid metabolism in naive CD8+ T cells and their impaired responsiveness to stimulation, characterized by low proliferative potential and susceptibility to apoptosis. Reversal of the bioenergetic anomalies with lipid-altering drugs, such as rosiglitazone, improved the functional capabilities of naive CD8+ T cells in elderly subjects. InterpretationInterventions that favor lipid catabolism may find utility as adjunctive therapies in the elderly to promote vaccine-induced immunity against emerging pathogens or tumors. FundingA full list of the funding sources is detailed in the Acknowledgment section of the manuscript. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSOld subjects are highly susceptible to infections and tumors and usually present with low responses to vaccine. This is mainly due to the age-related loss of primary immune resources, i.e. a quantitative decline of naive CD8+ T cells. Nonetheless, few studies have also underlined, within this cell subset, qualitative defects in elderly subjects. Added value of this studyConsidering the well-demonstrated link between nutrient usage and lymphocyte functions, we characterized the bioenergetics features of old naive CD8+ T cells. Our data show an age-dependent altered basal metabolism in this cell subset, mostly at the levels of fatty acids and mitochondrial functions. These alterations were associated with functional defects which were partially reverted through the use of lipid-lowering strategies. Implications of all the available evidenceThis study highlights the potential role of an altered cellular lipid metabolism in immunosenescence, providing clues to understand the epidemiological profile of emerging infections or tumors and to develop preventive and therapeutic strategies based on metabolic manipulation.

immunology↗