Both the pre-BCR and the IL-7Rα are essential for expansion at the pre-BII cell stagein vivo

Abstract

During B cell development, proliferative expansion takes place after expression of the pre-BCR. At this pre-BII cell stage, the IL-7Ra is also expressed. Some in vitro studies suggest that pre-BCR-dependent expansion relies on the IL-7Ra, and others that it does not. It has also been suggested that the pre-BCR mediates down-regulation of the IL7Ra. However, the in vivo relationship between the pre-BCR and the IL-7Ra has not been previously examined. Here, we have investigated this by establishing mice lacking both receptors. Our results show that in the absence of the IL-7Ra, the pre-BII population is reduced, as previously seen in mice lacking the pre-BCR, demonstrating that the IL-7Ra is important at this stage. A deficiency in both receptors results in a further reduction of the pre-BII cell population. We conclude that both the IL-7Ra and the pre-BCR are required for optimal pre-BII cell expansion. Furthermore, IL-7Ra expression levels are normal in pre-BCR-deficient mice, suggesting that the pre-BCR does not mediate its down-regulation. As a consequence of the absence of both receptors, the peripheral B cell pool is severely depleted, resulting in atypical splenic B cell structures and reduced serum Ig levels. IntroductionB lymphopoiesis takes place in the fetal liver and, postnatally, in the BM [1][2][3]. During early BM B cell development, critical checkpoints occur firstly after Ig heavy (H)-chain DJ H rearrangement and secondly after successful VDJ H rearrangement. Due to the inherent imprecision of the rearrangement process, each of these is followed by proliferative expansion at the pre-BI (DJ H ) and large pre-BII (VDJ H ) cell stages, which results in an increase in cell numbers and, consequently, the Ig repertoire. Functional VDJ H -rearrangement leads to expression of the lH chain, which, together with the surrogate light chain (SLC, comprised of VpreB and k5) [4, 5], forms the pre-B cell receptor (pre-BCR) [6][7][8]. After subsequent Ig light (L)-chain recombination, although not followed by an expansion phase, the end result is the production of large numbers of immature B cells, each carrying a unique BCR (IgM) on the cell surface. Immature B cells migrate to the spleen, where they mature and co-express IgD [9].Expansion at the pre-BI cell stage has been shown, both in vitro [10][11][12][13] and in vivo [14][15][16][17][18][19][20][21], to depend on the IL-7Ra [22]. Mice deficient in the IL-7Ra chain show a block in B cell development at the pre-BI stage. Although this block is complete in adult IL-7Ra -/-mice, Leukocyte signalingThe last two authors contributed equally to this work. [20,21]. The IL-7Ra chain heterodimerizes with the common gamma (c C ) chain [22,23] to form the receptor for IL-7, while together with the thymic stromal lymphopoietin (TSLP) receptor chain [24,25], it forms the receptor for TSLP. Expansion at the pre-BII stage is dependent on the expression of the pre-BCR. While a lack of the transmembrane region of the lH chain (lMT) leads to a complete block at the pre-BI stag...

Toll-like receptor 4-mediated signaling regulates IL-7-driven proliferation and differentiation of B-cell precursors

“…This is reminiscent of the synergism between pre-BCR and IL-7 signals that was revealed in previous studies. 16,33 Although signal transduction downstream of pre-BCR remains to be fully characterized, similar signaling complexes are formed following the engagement of BCR and pre-BCR. [34][35][36] Because TLR4 signaling is shown to synergize with BCR-delivered signals during the activation of mature B cells, 37,38 it would not be surprising if the TLR4 signaling pathway also interacts with pre-BCR signaling during pre-B-cell development.…”

Transient decrease in interleukin‐7 availability arrests B lymphopoiesis during pregnancy

“…Subsequently, the lack of B and T cell development in adult IL-7 or IL-7R genedeleted mice confirmed these results [13,14]. In the B cell lineage, IL-7Ra (CD127) begins to be expressed weakly on EPLM [4], and its expression increases, reaching a maximum on large pre-B2 cells [6,8]. Expression then decreases on subsequent stages to reach undetectable levels on mature B cells.…”

“…Expression then decreases on subsequent stages to reach undetectable levels on mature B cells. We and others have already shown, by both in vitro and in vivo methods, that IL-7 is responsible for the proliferation of pre-B1 cells and can improve the proliferation of pre-B2 cells [6,8,11,[15][16][17][18]. Even though it is largely accepted that IL-7 is crucial for B cell development, so far the exact nature of the BM stromal cells producing IL-7 and supporting B cell development awaits further characterization.…”

“…Upon maturation along the B cell pathway, EPLM cells acquire CD19 expression and are probably the direct precursors of pre-B1 cells. Dependent upon both pre-BCR and IL-7R signaling, pre-B1 cells then differentiate sequentially into large and then small pre-B2 cells [5][6][7][8]. Following subsequent immunoglobulin light-chain gene rearrangements, pre-B2 cells give rise to immature B cells which then emigrate via the blood to the spleen, where they complete their maturation through so-called transitional stages prior to becoming either mature follicular or marginal zone B cells [2].…”

Integrated signaling in developing lymphocytes

“…8,10,11 These cells and prevents generation of RAG DSBs at antigen receptor loci in actively dividing cells. Activation of the IL-7r in pre-B cells leads to phosphorylation and dimerization of STAT5, which results in nuclear translocation and initiation of gene expression.…”