19 research outputs found
Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells
Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cellâdependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5; ERK; PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10â and IL-21âmediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21âinduced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human
B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic
difference in the mechanism underlying differentiation of naive versus memory B cells.This work was funded by project and program grants from the National Health
and Medical Research Council (NHMRC) of Australia (to E.K. Deenick, C.S. Ma, D.A.
Fulcher, M.C. Cook, and S.G. Tangye) and the Rockefeller University Center for 541
Clinical and Translational science (5UL1RR024143 to J.L. Casanova). C.S. Ma is a
recipient of a Career Development Fellowship, L.J. Berglund is a recipient of a
Medical Postgraduate Scholarship, and S.G. Tangye is a recipient of a Principal
Research Fellowship from the NHMRC of Australia. L. Moens is the recipient of a
Postdoctoral Fellowship from the Research Foundation-Flanders (FWO), Belgium
The impact of transposable element activity on therapeutically relevant human stem cells
Human stem cells harbor significant potential for basic and clinical translational research as well as regenerative
medicine. Currently ~ 3000 adult and ~ 30 pluripotent stem cell-based, interventional clinical trials are ongoing
worldwide, and numbers are increasing continuously. Although stem cells are promising cell sources to treat a
wide range of human diseases, there are also concerns regarding potential risks associated with their clinical use,
including genomic instability and tumorigenesis concerns. Thus, a deeper understanding of the factors and
molecular mechanisms contributing to stem cell genome stability are a prerequisite to harnessing their therapeutic
potential for degenerative diseases. Chemical and physical factors are known to influence the stability of stem cell
genomes, together with random mutations and Copy Number Variants (CNVs) that accumulated in cultured human
stem cells. Here we review the activity of endogenous transposable elements (TEs) in human multipotent and
pluripotent stem cells, and the consequences of their mobility for genomic integrity and host gene expression. We
describe transcriptional and post-transcriptional mechanisms antagonizing the spread of TEs in the human genome,
and highlight those that are more prevalent in multipotent and pluripotent stem cells. Notably, TEs do not only
represent a source of mutations/CNVs in genomes, but are also often harnessed as tools to engineer the stem cell
genome; thus, we also describe and discuss the most widely applied transposon-based tools and highlight the
most relevant areas of their biomedical applications in stem cells. Taken together, this review will contribute to the
assessment of the risk that endogenous TE activity and the application of genetically engineered TEs constitute for
the biosafety of stem cells to be used for substitutive and regenerative cell therapiesS.R.H. and P.T.R. are funded by the Government of Spain (MINECO, RYC-2016-
21395 and SAF2015â71589-P [S.R.H.]; PEJ-2014-A-31985 and SAF2015â71589-
P [P.T.R.]). GGS is supported by a grant from the Ministry of Health of the
Federal Republic of Germany (FKZ2518FSB403)
Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells
Genetic evidence for paternal inheritance of the chloroplast in four Australian Callitris
Tritium separation from heavy water using a membrane containing deuterated manganese dioxide
4-Volt cathode materials for rechargeable lithium batteries wet-chemistry synthesis, structure and electrochemistry
Exposure assessment of phthalate esters in Japanese pregnant women by using urinary metabolite analysis
Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells
Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cellâdependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5; ERK; PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10â and IL-21âmediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21âinduced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic difference in the mechanism underlying differentiation of naive versus memory B cells