Ly49E expression points toward overlapping, but distinct, natural killer (NK) cell differentiation kinetics and potential of fetal versus adult lymphoid progenitors

Stevenaert, Frederik; Beneden, Katrien Van; Creus, An De; Debacker, Veronique; Plum, Jean; Leclercq, Georges

doi:10.1189/jlb.0902443

Cited by 20 publications

(20 citation statements)

References 36 publications

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“…The deficiency in expression of the other Ly49 family members in vivo could be a consequence of the relatively early time point examined in this experiment, as it is known that some family members, including Ly49A and D, are expressed at relatively late time points after BM reconstitution [25]. An inability to express appropriate levels of the Ly49 family members, with the exception of Ly49E, has also been observed in fetal-as well as embryonic stem cell-derived NK cells [25][26][27] and, very recently, in thymus-derived NK cells (Vosshenrich et al, in press), suggesting that the Pax5 -/-pro-B cell-derived NK cells differentiate along a similar pathway in vitro.…”

Section: Discussionmentioning

confidence: 98%

Transient Notch signaling induces NK cell potential in Pax5‐deficient pro‐B cells

Carotta

Brady

et al. 2006

Eur J Immunol

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Unlike early B/T cell development, NK cell lineage commitment is not well understood, with a major limitation being the lack of a robust culture system to assay NK cell progenitors. Here we have exploited the multi‐lineage potential of Pax5–/– pro‐B cells to establish an effective system to direct differentiation of progenitors into the NK cell lineage. Cultivation of Pax5–/– pro‐B cells on OP9 cells expressing the Notch ligand Delta‐Like1 (OP9‐DL1) in the presence of IL‐7 efficiently induced T and NK cell potential. For NK cells, Notch was only transiently required, as prolonged signaling decreased NK and increased T cell development. Pure NK cell populations could be obtained by the culture of these Notch signal‐experienced cells onto OP9 stroma and IL‐15. A similar transient exposure to Notch was also compatible with the differentiation of NK cells from hematopoietic progenitors, while sustained Notch signaling impaired NK cell generation. Pax5–/– pro‐B cell‐derived NK cells were cytotoxic, secreted cytokines and expressed all the expected NK cell‐specific surface markers examined except the Ly49 family, a phenotype similar to fetal NK cells. These data indicate that Notch signaling induces T/NK cell differentiation in Pax5–/– pro‐B cells that is strikingly similar to early thymopoiesis.

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Section: Discussionmentioning

confidence: 98%

Transient Notch signaling induces NK cell potential in Pax5‐deficient pro‐B cells

Carotta

Brady

et al. 2006

Eur J Immunol

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“…Previous studies have demonstrated that Ly49E is expressed abundantly, and in the absence of other Ly49 family members, by NK cells in fetal and neonatal mice (15,16), and also by V␥3-bearing subpopulations of ␥␦ T cells in vivo (18). Ly49E is acquired in a stochastic manner during the development of NK cells from immature progenitors, both in vitro (17) and in vivo (50), but is lost at some later point in development resulting in its being expressed on only a very small proportion of adult splenic NK cells. The detection of Ly49E in these previous studies relied on the use of the 4D12 mAb, which also reacts with Ly49C and perhaps with other members of the Ly49 family (16).…”

Section: Discussionmentioning

confidence: 99%

Multiple Cytokines Regulate the NK Gene Complex-Encoded Receptor Repertoire of Mature NK Cells and T Cells

Gays

Martin

Kenefeck

et al. 2005

The Journal of Immunology

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Mature NK cells comprise a highly diverse population of lymphocytes that express different permutations of receptors to facilitate recognition of diseased cells and perhaps pathogens themselves. Many of these receptors, such as those belonging to the NKRP1, NKG2, and Ly49 families are encoded in the NK gene complex (NKC). It is generally thought that these NKC-encoded receptors are acquired by a poorly understood stochastic mechanism, which operates exclusively during NK cell development, and that following maturation the repertoire is fixed. However, we report a series of observations that demonstrates that the mature NK cell repertoire in mice can in fact be radically remodeled by multiple cytokines. Thus, both IL-2 and IL-15 selectively induce the de novo expression of Ly49E on the majority of mature NK cells. By contrast, IL-4 not only blocks this IL-2-induced acquisition of Ly49E, but reduces the proportion of mature NK cells that expresses pre-existing Ly49 receptors and abrogates the expression of NKG2 receptors while leaving the expression of several NKRP1 receptors unaltered. IL-21 also abrogates NKG2 expression on mature NK cells and selectively down-regulates Ly49F. IL-4 and IL-21 additionally cause dramatic and selective alterations in the NKC-encoded receptor repertoire of IL-2-activated T cells but these are quite different to the changes induced on NK cells. Collectively these findings reveal an unexpected aspect of NKC receptor expression that has important implications for our understanding of the function of these receptors and of the genetic mechanisms that control their expression.

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“…[14][15][16]22,29,30 However, little is known about actual molecular signals that induce the expression and control the acquisition of Ly49 and CD94/NKG2 receptors. Recent studies on mice deficient for the transcription factors T-cell factor-1 (TCF-1), PU.1, and GATA3 indicated a role for these transcription factors in the modulation of expression of some Ly49 receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Acquisition of the different Ly49 members occurs in an orderly and time-dependent fashion, where Ly49A is the last receptor to be expressed, and where CD94/NKG2 expression is high at early time points and decreases thereafter. 22 Therefore, small differences in the rate of NK cell differentiation between both strains could explain the minor differences in Ly49A receptor and CD94/ NKG2 receptor repertoire. …”

mentioning

confidence: 99%

Ly49 and CD94/NKG2 receptor acquisition by NK cells does not require lymphotoxin-β receptor expression

Stevenaert

Beneden

Colvenaer

et al. 2005

Blood

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IntroductionLymphotoxin ␣ (LT␣), LT␤, and tumor necrosis factor ␣ (TNF␣) are structurally related cytokines belonging to the TNF ligand superfamily. 1 In soluble forms, LT␣ and TNF␣ homotrimers interact with TNF receptor I and II, leading to a variety of inflammatory responses. [2][3][4] LT␣ can also form a membrane-bound LT␣ 1 ␤ 2 heterotrimer that signals through the LT␤ receptor (LT␤R). 3,4 LIGHT, another member of the TNF superfamily, has also been identified as a ligand for the LT␤R. 5 While LT␣ and LT␤ are expressed in activated lymphocytes and natural killer (NK) cells, 6 the expression of LT␤R is restricted to nonlymphoid cells, including bone marrow (BM) stromal cells. 7 Previous studies in mice deficient for LT␣, LT␤, and LT␤R have shown a profound role for LT-LT␤R-mediated signaling in the secondary lymphoid organogenesis and function. Since lymph node development is not impaired in severe combined immunodeficient (SCID), double-negative recombination-activating gene 1 (RAG1 Ϫ/Ϫ ) and RAG2 Ϫ/Ϫ mice, it has been assumed that NK progenitor cells, which express LT␣ 1 ␤ 2 , are essential in secondary lymphoid formation. [8][9][10] NK cells represent an important component of the innate immune system and are able to lyse a variety of virally infected cells and tumor cells without prior sensitization. 11 Inhibitory and stimulatory receptors expressed on the surface of NK cells regulate NK cell cytotoxicity. In the mouse, the inhibitory receptors for major histocompatibility complex (MHC) class I molecules include the Ly49 and CD94/NKG2 receptor family (reviewed in Lanier 12 and Raulet et al 13 ). The signals inducing Ly49 receptor expression are poorly characterized, but BM stromal cells are indispensable for Ly49 receptor expression in vitro, [14][15][16] and an intact BM microenvironment is required for complete NK cell maturation in vivo. 17 Studies have shown that NK cell development and maturation are severely impaired in LT␣ Ϫ/Ϫ and LT␤R Ϫ/Ϫ mice, with reduced NK cell percentages in spleen, BM, and blood. 8,[18][19][20] However, because of higher leukocyte numbers in spleen and blood, 18,19 it is not always clear whether there was a similar reduction in the absolute NK cell number. Functionally, NK cells showed a reduced lytic capacity in vitro and an impaired antitumor function and recruitment of NK cells to lung and liver in vivo. 19 It has been indicated that the defect in NK cell development may primarily be due to defective BM stromal cells. 20 A model for the role of LT-LT␤R-mediated signaling in NK cell differentiation in BM has been proposed: contact of membrane-bound LT␣ 1 ␤ 2 -expressing hematopoietic progenitor cells with BM stromal cells activates the latter, which in turn induce interleukin 15 (IL-15) receptor expression on NK precursor cells. IL-15 is sufficient for the IL-15-responsive precursors to differentiate into immature NK1.1 ϩ NK cells independent of BM stromal cells. Later on, BM stromal cells are, by an unidentified mechanism, required for the differentiation 20 Since NK cell...

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Ly49E expression points toward overlapping, but distinct, natural killer (NK) cell differentiation kinetics and potential of fetal versus adult lymphoid progenitors

Cited by 20 publications

References 36 publications

Transient Notch signaling induces NK cell potential in Pax5‐deficient pro‐B cells

Transient Notch signaling induces NK cell potential in Pax5‐deficient pro‐B cells

Multiple Cytokines Regulate the NK Gene Complex-Encoded Receptor Repertoire of Mature NK Cells and T Cells

Ly49 and CD94/NKG2 receptor acquisition by NK cells does not require lymphotoxin-β receptor expression

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