B-1a Cells Acquire Their Unique Characteristics by Bypassing the Pre-BCR Selection Stage (original) (raw)
Related papers
2009
As many as 5-15% of B-1 cells in the peritoneal cavity of adult mice produce antibodies reactive to phosphatidylcholine (PtC) and the vast majority of them express B cell receptors (BCRs) composed of V H 11-mH chains utilizing the J H 1 segment and Vk9-L chains. This extremely skewed repertoire of PtCreactive B-1 cells is traditionally attributed to the expansion of particular clones in response to self or exogenous antigens. Here, we show that the strong bias toward the J H 1 usage among V H 11-mH chains is already established prior to the BCR assembly, namely at the transition from the large to the small pre-B cell stage during B cell ontogeny in the fetal liver. Among V H 11-mH clones isolated from large pre-B cells where the J H 1 skewing was not established yet, the J H 1 users showed the highest ability to form pre-B cell receptor (pre-BCR) and to induce cellular proliferation and differentiation when expressed in fetal liver pro-B cells. Thus, the J H 1 users were positively selected and amplified at the pre-BCR checkpoint. When co-expressed with Vk9-L chains to form BCR, the J H 1 users almost exclusively conferred the PtC reactivity on BCR even though other J H users could also form BCR on the cell surface. Therefore, the pre-BCR-mediated positive selection of the J H 1 users among V H 11-mH chains appears to be beneficial to the efficient generation of 'innate-type' PtC-reactive B cells during the fetal B cell development, even before the self-renewal or the antigen-driven clonal expansion of B-1 cells takes place in the peritoneal cavity.
Journal of Experimental Medicine, 1998
The expression of different sets of immunoglobulin specificities by fetal and adult B lymphocytes is a long-standing puzzle in immunology. Recently it has become clear that production of immunoglobulin heavy chain and subsequent assembly with a surrogate light chain to form the pre-B cell receptor complex is critical for development of B cells. Here we show that instead of promoting pre-B cell progression as in adult bone marrow, this complex inhibits pre-B cell growth in fetal liver. Curiously, we identify a fetal-associated V H 11 heavy chain that allows continued pre-B proliferation in fetal liver. Interestingly, this heavy chain does not associate efficiently with a surrogate light chain, providing a previously unrecognized mechanism for skewing the expression of distinctive V H genes toward fetal through early neonatal life.
Scientific Reports, 2016
Newborns are unable to mount antibody responses towards certain antigens. This has been related to the restricted repertoire of immunoglobulin (Ig) genes of their B cells. The mechanisms underlying the restricted fetal Ig gene repertoire are currently unresolved. We here addressed this with detailed molecular and cellular analysis of human precursor-B cells from fetal liver, fetal bone marrow (BM), and pediatric BM. In the absence of selection processes, fetal B-cell progenitors more frequently used proximal V, D and J genes in complete IGH gene rearrangements, despite normal Ig locus contraction. Fewer N-nucleotides were added in IGH gene rearrangements in the context of low TdT and XRCC4 expression. Moreover, fetal progenitor-B cells expressed lower levels of IL7Rα than their pediatric counterparts. Analysis of progenitor-B cells from IL7Rα-deficient patients revealed that TdT expression and N-nucleotides additions in Dh-Jh junctions were dependent on functional IL7Rα. Thus, IL7Rα affects TdT expression, and decreased expression of this receptor underlies at least in part the skewed Ig repertoire formation in fetal B-cell precursors. These new insights provide a better understanding of the formation of adaptive immunity in the developing fetus. During the second trimester of human fetal development, B cells are generated in the liver and bone marrow (BM), providing the neonate with a diverse immunoglobulin (Ig) repertoire. Still, antibody responses towards certain antigens (e.g. tetanus or diphtheria toxoid) are impaired in neonates, and the ability to respond is only acquired with age 1-3. Various processes can underlie this initial inability to mount such responses, including a "pre-mature" diversity of the Ig repertoire. B-cell development has been extensively studied in human postnatal BM, where 5 distinct stages can be identified. In the early pro-B and pre-BI cell stages, D to J gene rearrangements and V to DJ gene rearrangements are induced by the lymphoid-specific recombination activating gene proteins 1 and 2 (Rag1 and Rag2) in the Ig heavy chain (IGH) locus 4,5. Subsequently, the cells induce V to J gene rearrangements in their Ig light chain loci (IGK or IGL) as pre-B-II small cells and the complete Ig molecule is selected for functionality at the immature-B cell stage 6,7. The Rag-induced double stranded DNA breaks activate cell cycle checkpoint protein ATM and the non-homologous end joining (NHEJ) pathway 8-10 , which enhances diversity in the junctional region that encodes the antigen-binding complementary determining region (CDR)3. A central player is the lymphoid-specific deoxynucleotidyl transferase protein (TdT) that randomly adds N-nucleotides to the junction 11-13 .
Transitional B Cells in Early Human B Cell Development - Time to Revisit the Paradigm?
Frontiers in immunology, 2016
The B cell repertoire is generated in the adult bone marrow by an ordered series of gene rearrangement processes that result in massive diversity of immunoglobulin (Ig) genes and consequently an equally large number of potential specificities for antigen. As the process is essentially random, the cells exhibiting excess reactivity with self-antigens are generated and need to be removed from the repertoire before the cells are fully mature. Some of the cells are deleted, and some will undergo receptor editing to see if changing the light chain can rescue an autoreactive antibody. As a consequence, the binding properties of the B cell receptor are changed as development progresses through pre-B ≫ immature ≫ transitional ≫ naïve phenotypes. Using long-read, high-throughput, sequencing we have produced a unique set of sequences from these four cell types in human bone marrow and matched peripheral blood, and our results describe the effects of tolerance selection on the B cell repertoir...
The Journal of Immunology, 2013
During early stages of B-lineage differentiation in bone marrow, signals emanating from IL-7R and pre-BCR are thought to synergistically induce proliferative expansion of progenitor cells. Paradoxically, loss of pre-BCR–signaling components is associated with leukemia in both mice and humans. Exactly how progenitor B cells perform the task of balancing proliferative burst dependent on IL-7 with the termination of IL-7 signals and the initiation of L chain gene rearrangement remains to be elucidated. In this article, we provide genetic and functional evidence that the cessation of the IL-7 response of pre-B cells is controlled via a cell-autonomous mechanism that operates at a discrete developmental transition inside Fraction C′ (large pre-BII) marked by transient expression of c-Myc. Our data indicate that pre-BCR cooperates with IL-7R in expanding the pre-B cell pool, but it is also critical to control the differentiation program shutting off the c-Myc gene in large pre-B cells.
Innate pathways to B-cell activation and tolerance
Annals of The New York Academy of Sciences, 2010
B cells represent an important link between the adaptive and innate immune systems as they express both antigenspecific B-cell receptors (BCRs) as well as various Toll-like receptors (TLRs). Several checkpoints in B-cell development ensure that self-specific cells are eliminated from the mature B-cell repertoire to avoid harmful autoreactive responses. These checkpoints are controlled by BCR-mediated events but are also influenced by TLR-dependent signals from the innate immune system. Additionally, B-cell-intrinsic and extrinsic TLR signaling are critical for inflammatory events required for the clearance of microbial infections. Factors secreted by TLR-activated macrophages or dendritic cells directly influence the fate of protective and autoreactive B cells. Additionally, naive and memory B cells respond differentially to TLR ligands, as do different B-cell subsets. We review here recent literature describing intrinsic and extrinsic effects of TLR stimulation on the fate of B cells, with particular attention to autoimmune diseases.
Blood, 2009
To study B-cell development from bone marrow (BM), we generated recombination-activating gene 1 (Rag1)–targeted mice lacking mature lymphocytes. B-cell development can be induced in such mice by B cell–specific restoration of a functional Rag1 transcription unit. Follicular and marginal zone B cells populated the spleen when Rag1 expression was permitted. Notably, the peritoneal cavity was dominated by bona fide B-1a cells, as judged by surface markers and functional properties. These BM-derived B-1a cells exhibited a polyclonal VDJ repertoire with substantial N nucleotide insertions. Nevertheless, physiologic frequencies of phosphatidylcholine-specific B cells were detected. Importantly, the BM of young and 5-month-old mice was indistinguishable with regard to the potential to generate B-1a cells.