Partial block in B lymphocyte development at the transition into the pre-B cell receptor stage in Vpre-B1-deficient mice

The surrogate light chain (SL) is composed of two polypeptides, Vpre-B and lambda5. In large pre-BII cells the SL chain associates with Ig mu heavy chain (muH) to form the pre-B cell receptor (pre-BCR). In mice there are two Vpre-B genes which are 98% identical within the coding regions. The two genes are co-expressed at the RNA level and encode functional proteins that can assemble with lambda5. However, it is not known whether both gene products serve the same function in vivo. Here we have established mice that lack the Vpre-B1 gene (VpreB1(-/-)), but still express the Vpre-B2 gene, both as RNA and protein. In Vpre-B1(-/-) mice, the bone marrow cellularity and the percentage of B220+ cells is normal. However, among the B220+ cells, the percentage of pre-BI cells is increased, and the percentage of pre-BII and immature B cells is slightly decreased, suggesting that the lack of Vpre-B1 causes a partial block at the transition from pre-BI to pre-BII cells, i.e. into the pre-BCR stage. The number of cells that produce a functional pre-BCR is thus lower, but the cells that reach this stage are normal as they can be expanded by proliferation and then differentiate into more mature cells. The spleens of Vpre-B1 homozygous mutant mice show normal numbers of B and T lymphocytes. Moreover, the Ig loci are allelicly excluded and the homozygous mutant mice respond with normal levels of antigen-specific antibodies to T-dependent antigens. These results demonstrate that VpreB2 alone is capable of supporting B lymphocyte development in the bone marrow and can give rise to immuno-competent cells in the periphery.     

Notch signaling in lymphocyte development

Cytokine and antigen receptor signals play well-characterized roles in promoting the survival and maturation of T and B lymphocyte progenitors through sequential developmental stages. Emerging studies suggest equally important roles for more ancient signaling pathways that evolved prior to the adaptive immune system in jawed vertebrates. In particular, there are at least two essential functions for the highly conserved Notch signaling pathway in lymphocyte development. First, Notch signals are essential for the development of T cell progenitors in the thymus and intestinal epithelium. Second, Notch signals are required to suppress B cell development in the thymus. This review will focus on focus on recent advances in our understanding of how Notch signaling regulates this developmental switch, as well as how Notch might regulate subsequent survival and cell fate decisions in developing T cells.     

Gut intraepithelial lymphocyte development

CD8alphabeta(+) and CD4(+) intraepithelial lymphocytes, the progeny of double-positive thymocytes, are oligoclonal T-cell populations that have accumulated in the gut wall as the result of repeated antigenic stimulations, which lead to rounds of traffic through the lymph/blood circuit ending in an alpha4beta7-integrin-driven homing all along the gut mucosa. In contrast, CD8alphaalpha(+) intraepithelial lymphocytes, which may be TCRgammadelta(+) or alphabeta(+), result in part from local differentiation in the gut, but studies comparing euthymic and athymic mice suggest a thymic double-negative origin for many of them.     

B-cell antigen-receptor signalling in lymphocyte development

Signalling through the B-cell antigen receptor (BCR) is required throughout B-cell development and peripheral maturation. Targeted disruption of BCR components or downstream effectors indicates that specific signalling mechanisms are preferentially required for central B-cell development, peripheral maturation and repertoire selection. Additionally, the avidity and the context in which antigen is encountered determine both cell fate and differentiation in the periphery. Although the signalling and receptor components required at each stage have been largely elucidated, the molecular mechanisms through which specific signalling are evoked at each stage are still obscure. In particular, it is not known how the pre-BCR initiates the signals required for normal development or how immature B cells regulate the signalling pathways that determine cell fate. In this review, we will summarize the recent studies that have defined the molecules required for B-cell development and maturation as well as the theories on how signals may be regulated at each stage.     

Molecular events in the development of the lymphocyte repertoire.

Last autumn, an international cast of molecular geneticists and immunologists coalesced around the comfortable Bishenberg Centre in the hills of Alsace to assess various aspects of the expression and development of the lymphocyte repertoire*. Here, progress in the understanding of control of genomic rearrangements and development of the lymphocyte repertoire are described.     

Age-related changes in lymphocyte development and function

The effects of aging on the immune system are widespread and extend from hematopoietic stem cells and lymphoid progenitors in the bone marrow and thymus to mature lymphocytes in secondary lymphoid organs. These changes combine to result in a diminution of immune responsiveness in the elderly. This review aims to provide an overview of age-related changes in lymphocyte development and function and discusses current controversies in the field of aging research.     

Notch signaling in lymphocyte development and function

Over the past few years, the crucial role of Notch signaling in multiple stages of T-cell development has become apparent. Recent studies have helped to define more precisely the functions and components of the Notch signaling pathway in T-cell development, including during the T versus B fate decision and in early CD4(-)CD8(-)double-negative thymocytes. In addition, new evidence points to a requirement for Notch2 in the development of marginal zone B cells. Finally, recent studies have provided our first glimpse into the complex and paradoxical roles of Notch signaling in the activation and differentiation of mature T cells.     

Lipid-cytokine-chemokine cascades orchestrate leukocyte recruitment in inflammation

Chemoattractants are pivotal mediators of host defense, orchestrating the recruitment of immune cells into sites of infection and inflammation. Chemoattractants display vast chemical diversity and include bioactive lipids, proteolytic fragments of serum proteins, and chemokines (chemotactic cytokines). All chemoattractants induce chemotaxis by activating seven-transmembrane-spanning GPCRs expressed on immune cells, establishing the concept that all chemoattractants are related in function. However, although chemoattractants have overlapping functions in vitro, recent in vivo data have revealed that they function, in many cases, nonredundantly in vivo. The chemically diverse nature of chemoattractants contributes to the fine control of leukocyte trafficking in vivo, with sequential chemoattractant use guiding immune cell recruitment into inflammatory sites. Lipid mediators frequently function as initiators of leukocyte recruitment, attracting the first immune cells into tissues. These initial responding immune cells produce cytokines locally, which in turn, induce the local release of chemokines. Local chemokine production then markedly amplifies subsequent waves of leukocyte recruitment. These new discoveries establish a paradigm for leukocyte recruitment in inflammation--described as lipid-cytokine-chemokine cascades--as a driving force in the effector phase of immune responses.     

The role of the non-homologous end-joining pathway in lymphocyte development

Summary: One of the most toxic insults a cell can incur is a disruption of its linear DNA in the form of a double‐strand break (DSB). Left unrepaired, or repaired improperly, these lesions can result in cell death or neoplastic transformation. Despite these dangers, lymphoid cells purposely introduce DSBs into their genome to maximize the diversity and effector functions of their antigen receptor genes. While the generation of breaks requires distinct lymphoid‐specific factors, their resolution requires various ubiquitously expressed DNA‐repair proteins, known collectively as the non‐homologous end‐joining pathway. In this review, we discuss the factors that constitute this pathway as well as the evidence of their involvement in two lymphoid‐specific DNA recombination events.