NK cells in the CD19- B220+ bone marrow fraction are increased in senescence and reduce E2A and surrogate light chain proteins in B cell precursors

Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
Mechanisms of ageing and development (Impact Factor: 3.4). 07/2009; 130(6):384-92. DOI: 10.1016/j.mad.2009.03.002
Source: PubMed


E2A encoded proteins, key transcriptional regulators in B lineage specification and commitment, have been shown to decrease in B cell precursors in old age. E2A regulates genes encoding the surrogate light chain proteins lambda5 and VpreB. In old age, B cell precursors express less surrogate light chain and this results in compromised pre-B cell receptor function and diminished expansion of new pre-B cells in senescence. Herein, we show that aged bone marrow has increased Hardy Fraction A (CD19(-) B220(+)) cells, including NK cells, that can inhibit both E47 (E2A) protein and surrogate light chain protein expression in B cell precursors. In vitro, NK-associated inhibition of E47 protein is contact-independent and partially reversed by neutralization of TNFalpha. In vivo, depletion of NK cells in aged mice by treatment with anti-asialo GM1 antibody led to restoration of surrogate light chain protein levels to that typical of young B cell precursors. These studies suggest that NK cells, within the CD19(-) B220(+) bone marrow cell fraction, may contribute to a bone marrow microenvironment that has the potential to negatively regulate E47 (E2A) as well as surrogate light chain levels in B cell precursors in old age.

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    • "For example, we have previously shown that TNFaproducing NK cells are elevated in the bone marrow of aged mice (King et al., 2009). In old age, a variety of cells, including adipose cells, macrophages, NK cells, as well as B cells produce TNFa (Wu et al., 2007; King et al., 2009; Frasca et al., 2012; Ratliff et al., 2013). Dissecting the relative importance of each cell source and cytokine are studies which merit further efforts. "
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    ABSTRACT: In aged mice, new B-cell development is diminished and the antibody repertoire becomes more autoreactive. Our studies suggest that (i) apoptosis contributes to reduced B lymphopoiesis in old age and preferentially eliminates those B-cell precursors with higher levels of the surrogate light chain (SLC) proteins (λ5/VpreB) and (ii) λ5(low) B-cell precursors generate new B cells which show increased reactivity to the self-antigen/bacterial antigen phosphorylcholine (PC). Pro-B cells in old bone marrow as well as pro-B cells from young adult λ5-deficient mice are resistant to cytokine-induced apoptosis (TNFα; TGFβ), indicating that low λ5 expression in pro-B cells is sufficient to cause increased survival. Transfer of TNFα-producing 'age-associated B cells' (ABC; CD21/35(-) CD23(-) ) or follicular (FO) B cells from aged mice into RAG-2 KO recipients led to preferential loss of λ5(high) pro-B cells, but retention of λ5(low) , apoptosis-resistant pro-B cells. In old mice, there is increased reactivity to PC in both immature bone marrow B cells and mature splenic FO B cells. In young mice, absence of λ5 expression led to a similar increase in PC reactivity among bone marrow and splenic B cells. We propose that in old age, increased apoptosis, mediated in part by TNFα-producing B cells, results in preferential loss of SLC(high) pro-B cells within the bone marrow. Further B-cell development then occurs via an 'SLC(low) ' pathway that not only impairs B-cell generation, but promotes autoreactivity within the naïve antibody repertoires in the bone marrow and periphery. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging cell 02/2015; 14(3). DOI:10.1111/acel.12302 · 6.34 Impact Factor
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    • "First, we observed that aged mice have reduced NK cells in major peripheral tissues but not in the bone marrow. There are previous reports that aged mice have reduced NK cells in their spleen (Beli et al., 2011; Dussault and Miller, 1994; Fang et al., 2010; Saxena et al., 1984) and increased NK cells in their bone marrow (King et al., 2009). Yet, because other studies report no age-related differences in NK cells (Dong et al., 2000; Koo et al., 1982; Nogusa et al., 2008; Plett and Murasko, 2000) and most human studies report increased numbers of circulating NK cells with aging (Almeida-Oliveira et al., 2011; Borrego et al., 1999; Facchini et al., 1987; Lutz et al., 2005; Sansoni et al., 1993; Vitale et al., 1992) the effect of aging on NK cell distribution required more attention. "
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    ABSTRACT: The effect of aging on natural killer cell homeostasis is not well studied in humans or in animal models. We compared natural killer (NK) cells from young and aged mice to investigate age-related defects in NK cell distribution, and development. Our findings indicate aged mice have reduced NK cells in most peripheral tissues, but not in bone marrow. Reduction of NK cells in periphery was attributed to a reduction of the most mature CD11b(+) CD27(-) NK cells. Apoptosis was not found to explain this specific reduction of mature NK cells. Analysis of NK cell development in bone marrow revealed that aged NK cells progress normally through early stages of development, but a smaller percentage of aged NK cells achieved terminal maturation. Less mature NK cells in aged bone marrow correlated with reduced proliferation of immature NK cells. We propose advanced age impairs bone marrow maturation of NK cells, possibly affecting homeostasis of NK cells in peripheral tissues. These alterations in NK cell maturational status have critical consequences for NK cell function in advanced age: reduction of the mature circulating NK cells in peripheral tissues of aged mice affects their overall capacity to patrol and eliminate cancerous and viral infected cells.
    Mechanisms of ageing and development 12/2013; 135(1). DOI:10.1016/j.mad.2013.11.007 · 3.40 Impact Factor
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    • "This may not only affect the numbers of B-cell precursors available for further development along the B lineage, but also may affect such functions as read-out of the antibody repertoire in old mice as we (Wilson et al., 2005; Alter-Wolf et al., 2009) and others (Klinman & Kline, 1997) have reported. As we have previously observed, TNFa may diminish levels of the surrogate light chain k5 in pro-B cells (King et al., 2009) and this may compromise the pre-B-cell receptor checkpoint and influence l heavy chain selection. Therefore, ABC, as they become more prevalent within the spleen and the bone marrow, may comprise a B-cell subset capable of inappropriate " feedback " inhibition of B lymphopoiesis in old age. "
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    ABSTRACT: Aged mice exhibit ~ 5-10 fold increases in an ordinarily minor CD21/35(-) CD23(-) mature B cell subset termed age-associated B cells (ABC). ABC from old, but not young, mice induce apoptosis in pro-B cells directly through secretion of TNFα. In addition, aged ABC, via TNFα, stimulate bone marrow cells to suppress pro-B cell growth. ABC effects can be prevented by the anti-inflammatory cytokine IL-10. Notably, CD21/35(+) CD23(+) follicular (FO) splenic and FO-like recirculating bone marrow B cells in both young and aged mice contain a subpopulation which produces IL-10. Unlike young adult FO B cells, old FO B cells also produce TNFα; however, secretion of IL-10 within this B cell population ameliorates the TNFα-mediated effects on B cell precursors. Loss of B cell precursors in the bone marrow of old mice in vivo was significantly associated with increased ABC relative to recirculating FO-like B cells. Adoptive transfer of aged ABC into RAG-2 KO recipients resulted in significant losses of pro-B cells within the bone marrow. These results suggest that alterations in B cell composition during old age, in particular the increase in ABC within the B cell compartments contribute to a pro-inflammatory environment within the bone marrow. This provides a mechanism of inappropriate B cell "feedback" which promotes down-regulation of B lymphopoiesis in old age. © 2013 Blackwell Publishing Ltd/Anatomical Society.
    Aging cell 02/2013; 12(2). DOI:10.1111/acel.12055 · 6.34 Impact Factor
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