A Unique Role for the λ5 Nonimmunoglobulin Tail in Early B Lymphocyte Development

Vettermann, Christian; Herrmann, Kai; Albert, Christine M.; Roth, Edith; Bösl, Michael R.; Jäck, Hans‐Martin

doi:10.4049/jimmunol.181.5.3232

Cited by 27 publications

(20 citation statements)

References 62 publications

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“…Cells that have undergone a successful V to D-J recombination are selected, and the expression of the pre-BCR mediates their proliferative expansion [1,4,12,13,[25][26][27][28]. In mice lacking the surrogate light chain components, and thus unable to express the pre-BCR, this selection and expansion process fails to operate, resulting in the generation of fewer immature and mature B cells [1,[12][13][14]29].…”

Section: Tolerance Checkpoints In B-cell Development Large Pre-bii Cellsmentioning

confidence: 99%

Tolerance checkpoints in B‐cell development: Johnny B good

et al. 2009

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B-cell development up to the immature B-cell stage takes place in the bone marrow, while final maturation into mature B cells occurs in the spleen. During differentiation, the precursor and immature B cells have to pass several checkpoints, including those in which they are censored for being auto-reactive, and therefore being potentially dangerous. Numerous studies have shown that the immature B-cell stage in the bone marrow and the transitional B-cell stages in the spleen comprise distinct checkpoints at which autoreactivity is censored. Recently, evidence has been provided that the large pre-BII stage in the bone marrow, at which the pre-BCR is expressed, is yet another B-cell tolerance checkpoint. Here, we review these findings and speculate on directions for possible further experimentation.Key words: B cells . Negative selection . Positive selection . Receptor editing . Tolerance Introduction B-cell development, as it takes place in the bone marrow and spleen, can be subdivided into various stages based on the expression of different cell-surface and intra-cellular markers, the cell cycle profile and the rearrangement status of the cell's Ig-heavy (IgH) and Ig-light (IgL) chains [1][2][3][4]. In Fig. 1, the different stages of B-cell development in the bone marrow and spleen and the most important cell-surface markers by which different subpopulations can be distinguished are depicted. Moreover, the stages in which censoring for auto-reactivity takes place are shown in gray.The earliest B-lineage cell type found in the bone marrow is the pro/pre-BI cell. This cell type is characterized by the expression of CD19 and CD117 (c-kit) and the IgH chain loci are in a rearranged D-J configuration [4][5][6]. Under physiological conditions, these cells are already committed to the B-cell lineage. However, their commitment can be reversed by the ablation of the B-cell identity gene Pax5 [7][8][9]. Pro/pre-BI cells are the direct precursors of large pre-BII cells, which have lost CD117 expression and gained the expression of CD25 [3]. At this stage of differentiation, the IgH chain loci are V to D-J rearranged and those that have done this successfully (synthesized a m-heavy (mH) chain) are positively selected within this compartment. This positive selection is mediated by the pre-BCR, which is composed of the mH chain and the surrogate light chain proteins . Moreover, the pre-BCR induces a strong proliferation of these positively selected pre-B cells [12,13]. A very recent report indicates that the pre-BCR might also be involved in the censoring of B-cell auto-reactivity [16]. These findings will be discussed in the section Large pre-BII cells.Pre-BCR signaling down-modulates transcription of the surrogate light chain genes , and thereby extinguishes its own expression. Upon down-modulation of surface pre-BCR expression, cells stop proliferating and enter the small pre-BII compartment [3]. At this developmental stage, [18][19][20]. It is at this stage of development that, for the first time, cells are censored for t...

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Section: Tolerance Checkpoints In B-cell Development Large Pre-bii Cellsmentioning

confidence: 99%

Tolerance checkpoints in B‐cell development: Johnny B good

et al. 2009

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“…3 Expression of the pre-BCR represents a crucial checkpoint during B-cell development as this receptor controls pre-BII-cell development and the selection of the Ig repertoire. 4 The galectin-1 (GAL1) lectin and heparan sulfates, produced by the BM microenvironment, have been reported to bind to the pre-BCR, [5][6][7] and GAL1 was shown to promote pre-BCR clustering and signaling. 5 GAL1 binds to the SLC by a direct protein/protein interaction and to glycosylated integrins via the recognition of ␤-galactosides.…”

Section: Introductionmentioning

confidence: 99%

Galectin-1–expressing stromal cells constitute a specific niche for pre-BII cell development in mouse bone marrow

Mourcin

Breton

Tellier

et al. 2011

Blood

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In the bone marrow (BM), stromal cells constitute a supportive tissue indispensable for the generation of pro-B/pre-BI, pre-BII, and immature B lymphocytes. IL-7-producing stromal cells constitute a cellular niche for pro-B/pre-BI cells, but no specific stromal cell microenvironment was identified for pre-BII cells expressing a functional pre-B cell receptor (pre-BCR). However expression of the pre-BCR represents a crucial checkpoint during B-cell development. We recently demonstrated that the stromal cell derived-galectin1 (GAL1) is a ligand for the pre-BCR, involved in the proliferation and differentiation of normal mouse pre-BII cells. Here we show that nonhematopoietic osteoblasts and reticular cells in the BM express GAL1. We observed that pre-BII cells, unlike the other B-cell subsets, were specifically localized in close contact with GAL1 ؉ reticular cells. We also determined that IL-7 ؉ and GAL1 ؉ cells represent 2 distinct mesenchymal populations with different BM localization. These results demonstrate the existence of a pre-BII specific stromal cell niche and indicate that early B cells move from IL-7 ؉ to GAL1 ؉ supportive BM niches during their development. (Blood. 2011; 117(24):6552-6561) IntroductionThe bone marrow (BM) is the primary site of hematopoiesis after birth. Hematopoietic stem cells (HSCs) and hematopoietic progenitors are located in close contact with a special stromal microenvironment, known as niches, composed of mesenchymal cells, osteoblasts, endothelial cells, and adipocytes, indispensable for their differentiation. 1,2 Recent reports indicate that the spatial repartition of BM stromal cells and hematopoietic progenitors follows a coordinated regulation. 3 HSCs are in contact with osteoblasts on bone surfaces and endothelial cells lining sinusoids, and move near CXCL12 ϩ reticular stromal cells while they differentiate. In this tissue, B-cell differentiation is also a highly regulated process, which generates widely diversified immature B cells tolerant to self. Stage-specific cellular niches have been identified for the first steps of the B lymphopoiesis. 2 The earliest B220 ϩ cKit ϩ pro-B/pre-BI cells undergoing immunoglobulin H (IgH) gene rearrangements locate near IL-7-producing stromal cells. At the next step, when a functional Ig chain is produced and associated with the surrogate light chain (SLC) composed of 5 and VpreB and with the CD79a/CD79b signaling complex, the pre-B-cell receptor (pre-BCR) is formed and expressed at the surface of pre-BII cells. At this stage, cells leave IL-7-expressing stromal cells, but no specific pre-BII cellular niche has yet been identified. 3 Expression of the pre-BCR represents a crucial checkpoint during B-cell development as this receptor controls pre-BII-cell development and the selection of the Ig repertoire. 4 The galectin-1 (GAL1) lectin and heparan sulfates, produced by the BM microenvironment, have been reported to bind to the pre-BCR, [5][6][7] and GAL1 was shown to promote pre-BCR clustering and signaling. 5 GAL1 binds to the SLC ...

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“…Both constitutive 12,13 and ligand-induced 3,14 signaling have been described. In the mouse, Bradl et al 4 and Vettermann et al 5 showed that pre-BCR binding to stromal cells required the N-terminal unique region of 5 (5UR) and stroma cell-associated HS. In humans, we reported that GAL1 binds to the 5UR by a protein/protein interaction but also to glycosylated integrins present on stromal and pre-B cells.…”

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confidence: 99%

“…However galectin-1 (GAL1) and heparan sulfates (HSs), produced by the BM microenvironment, have been described to bind to the pre-BCR. [3][4][5] Pre-BCR expression represents a crucial step in B-cell development as it controls pre-BII-cell proliferation and differentiation. 6 Pre-BCRs also mediate allelic exclusion at the IgH locus 7,8 and selection of the Ig chain repertoire, 9 leading to the counterselection of autoreactive Ig chains.…”

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Impaired B-cell development at the pre-BII-cell stage in galectin-1–deficient mice due to inefficient pre-BII/stromal cell interactions

Espéli

Mancini

Breton

et al. 2009

Blood

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Activation of the pre-B-cell receptor (pre-BCR) in the bone marrow depends on both tonic and ligand-induced signaling and leads to pre-BII-cell proliferation and differentiation. Using normal mouse bone marrow pre-BII cells, we demonstrate that the ligand-induced pre-BCR activation depends on pre-BCR/galectin-1/integrin interactions leading to pre-BCR clustering at the pre-BII/stromal cell synapse. In contrast, heparan sulfates, shown to be pre-BCR ligands in mice, are not implicated in pre-BCR relocalization. Inhibition of pre-BCR/galectin-1/integrin interactions has functional consequences, since pre-BII-cell proliferation and differentiation are impaired in an in vitro B-cell differentiation assay, without affecting cellular apoptosis. Most strikingly, although galectin-1-deficient mice do not show an apparent B-cell phenotype, the kinetics of de novo B-cell reconstitution after hydroxyurea treatment indicates a specific delay in pre-BII-cell recovery due to a decrease in pre-BII-cell differentiation and proliferation. Thus, although it remains possible that the pre-BCR interacts with other ligands, these results highlight the role played by the stromal cell-derived galectin-1 for the efficient development of normal pre-BII cells and suggest the existence of pre-BII-specific stromal cell niches in normal bone marrow.

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A Unique Role for the λ5 Nonimmunoglobulin Tail in Early B Lymphocyte Development

Cited by 27 publications

References 62 publications

Tolerance checkpoints in B‐cell development: Johnny B good

Tolerance checkpoints in B‐cell development: Johnny B good

Galectin-1–expressing stromal cells constitute a specific niche for pre-BII cell development in mouse bone marrow

Impaired B-cell development at the pre-BII-cell stage in galectin-1–deficient mice due to inefficient pre-BII/stromal cell interactions

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