The role of homotypic interactions in the differentiation of B cell precursors (original) (raw)
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In-vitro analyses of mechanisms of B-cell development
Seminars in Immunology, 1995
B-cell lymphopoiesis in vivo is vq complex due to the influences of cooperating cells, qtokines and other receptor-ligand interactions which appear to occur develojnnentally at daffment cellular stages. Therefore in-vitro models will help to unravel this complex situation. Here, we review our and others' work on in-vitro models of B-cell development. The role of stromal cells, cytokines, surrogate light chain and wducts of rearranged Ig-loci in the o!evela,bmentally different cellular stages will be discussed.
Analysis of the molecular interactions regulating murine B cell development
2000
The proliferation, survival and differentiation of B cell precursors depends on extracellular signals provided by cells within the microenvironment. Cell-bound and secreted molecules direct B lineage progression and regulate the selection of clones from which the immune repertoire emerges. In fact, a myriad of signals derived from B cell progenitors themselves and the microenvironment, in which they develop, cooperatively regulate the progression of progenitors along the B lineage pathway. In this thesis, I describe several new molecular interactions that had previously not been considered to play a role in the early B cell differentiation process. I first characterize the cloning of a gene encoding a sialic acid specific 9-0-acetylesterase that was isolated by differential display analysis of a preBCR-proB cell line and a preBC~* preB cell line. Differential expression is confirmed by the analysis of several B cell lines and primary B lineage cells. Furthermore, the isolation of various cDNA clones with differing 5' sequences suggests an additional level of transcriptional regulation. This finding directs my studies to an examination of the B lineage-specific, sialic acid-binding lectin CD22, whose interactions are modified by 9-0-acetylation. In contrast to previous reports, I show that surface CD22 is expressed at an early stage of development. The study of CD22, whose ligands are also expressed at an early stage of development, finally leads to an analysis of the role of homotypic B cell precursor interactions during B cell development. Using an in vibo assay system I demonstrate that interactions between B cell precursors themselves promote their further development to a mature B cell stage. That preB-preB interactions promote or regulate the critical preBCR-driven signal is suggested by the dramatic inhibition of maturation observed upon blocking p heavy chain cell surface interactions. In summary, these results suggest two novel means of regulating the B cell differentiation process: the regulation of early CD22 interactions through 9-0-acetylation and the generation of differentiation signals through homotypic B cell precursor interactions.
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.
The Journal of Experimental Medicine, 1999
Mice expressing the immunoglobulin (Ig) heavy (H) chain variable (V) region from a rearranged VH12 gene inserted into the IgH locus generate predominantly B-1 cells, whereas expression of two other VH region transgenes (VHB1-8 and VHglD42) leads to the almost exclusive generation of conventional, or B-2, cells. To determine the developmental potential of B cells bearing two distinct B cell antigen receptors (BCRs), one favoring B-1 and the other favoring B-2 cell development, we crossed VH12 insertion mice with mice bearing either VHB1-8 or VHglD42. B cells coexpressing VH12 and one of the other VH genes are readily detected in the double IgH insertion mice, and are of the B-2 phenotype. In mice coexpressing VH12, VHB1-8 and a transgenic κ chain able to pair with both H chains, double H chain–expressing B-2 cells, and B-1 cells that have lost VHB1-8 are generated, whereas VHB1-8 single producers are undetectable. These data suggest that B-1 but not B-2 cells are selected by antigeni...
Characterization of a presecretory phase in B-cell differentiation
Proceedings of the National Academy of Sciences, 1989
We have identified and characterized an inducible in vitro subclone of the CH12 B-cell lymphoma, CH12-LBK, which appears to represent a transitional phase in the B-cell differentiation pathway. This phase, which we call the "presecretory" phase, falls between replicating B cells that are not secreting antibodies and B cells that secrete antibody at a high rate. Presecretory cells are characterized by abundant steady-state levels of immunoglobulin and joining (J) chain transcripts and of protein but low levels of mouse mammary tumor virus envelope transcripts and low rates of immunoglobulin secretion. Additional stimulation is required for presecretory cells to differentiate into cells that secrete antibodies at a high rate. The existence of cells with this phenotype suggests that high-level expression of immunoglobulin and J-chain protein does not necessarily commit a B cell to polymerize and secrete multimeric immunoglobulin. Rather, other gene products, expressed after i...
Early and late B-cell development in the mouse
Current Biology, 1992
A common principle in B-cell development is the stringent selection of cells expressing appropriate antibody V regions as surface receptors. Cells failing to do so appear destined to rapid death. These lifedeath decisions are mediated by signals whose nature is not yet understood but whose generation involves immunoglobulin receptor complexes on B cells and B-cell progenitors.