ReviewDevelopment and function of B-1 cells: Commentary
Introduction
The term ‘B-1’ was originally proposed to describe a type of distinctive fetal B cell development in the mouse, different from ‘B-2’ cells generated in adult bone marrow. Many of the fetal-generated B cells express CD5, whereas few cells of this phenotype arise during bone marrow development in adult animals. Thus the B-1/B-2 nomenclature was suggested to replace an earlier scheme based on surface phenotype alone: CD5+ B cells compared with CD5− B cells (sometimes called ‘conventional B cells’). Recent data reveal differences between B-1 (fetal) compared with B-2 (adult) B cell development in terms of initial repertoire establishment and cellular selection. Specifically, it appears that CD5 induction may be a consequence of positive selection in B-1 development resulting in enrichment of autoreactive B cells in this population. Such a requisite positive selection step would explain accumulating data on B-1 cell deficiency in diverse genetically engineered mice containing mutations that disrupt BCR signaling or in animals with immunoglobulin genes of ‘inappropriate’ specificity that preclude this selection. Interestingly, recent data also suggest the possibility of the generation of autoreactive ‘B1-like’ CD5− B cells during B-2 development — possibly by disregulation of normal tolerance mechanisms. This review mainly focuses on the mouse B-1 paradigm as currently debated, discussing data from the viewpoint of positive selection in B cell development. We also introduce recent information on the functional significance of B-1 cells in serum autoantibody production, mucosal immunity and disregulated B cell growth.
Section snippets
Distinct fetal and adult B cell development, as B-1 or B-2 cells
Although previous cell transfer experiments have revealed the fetal/neonatal generation of most CD5+ B cells, an important unresolved question is whether all CD5+ phenotype B cells found in mice with pathology (such as the autoimmune NZB strain) can be equated with those of fetal/neonatal origin in normal mice [1]. Furthermore, as more genetically engineered mice with aberrant BCR signaling or repertoire diversity are produced, the interpretation of results relating to normal B-1 development
Regulation of self-reactivity: the role of CD5
The significance of CD5 expression in B cell positive selection remains to be firmly established, since anti-PtC or ATA B cell accumulation and natural serum secretion can occur in CD5 knockout mice at levels comparable to wild-type [2]. However, it is likely that CD5 induction does have significance in self-regulation of autoreactivity after B-1 cells mature — such as an elimination of B-1 cells rendered hyperactive — as previously suggested by prevention of the apoptosis that is normally
The peritoneal cavity and autoreactive B cells
Honjo and co-workers 36, 37 have provided a series of experiments demonstrating the pathogenic role of peritoneal cavity B cells with an antierythrocyte-autoantibody transgenic mouse model. In contrast to the deletion of such B cells in the spleen, self-reactive B cells are present in the peritoneal cavity. They show predominantly a B-1b phenotype, with the potential to secrete antierythrocyte autoantibody following lipopolysaccharide, IL-5 or IL-10 administration. Overexpression of IL-5
Production of serum immunoglobulin
B-1 cells contribute to the production of serum immunoglobulin and natural autoantibody. B-1-associated natural anti-PtC autoantibody plays a role in defense against systemic bacterial infection, as demonstrated by an anti-PtC reconstitution experiment in mice deficient in IgM secretion [41]. In such secretion-deficient mice the frequency of B-1 cells is increased [42], suggesting that B-1 cell frequency may be controlled by a secreted IgM feedback mechanism. The contribution of B-1 cells to
Aging and tumors
There have been continuing efforts to understand the oligoclonal nature of B cells in aged animals, in terms of VH gene diversity [49] and CDR3 length [50]. Such analyses suggest that the progeny of both B-1 and B-2 may be involved in B cell expansion and also plasma-cell accumulation [50]. A problem with aged mice has been the fidelity of surface phenotype, since CD5 expression can be lost after mitogenic stimulation. Neverthetheless, a homeostatic mechanism appears to be involved in
Conclusions
B cell development includes several critical stages involving initial establishment of the immunoglobulin repertoire and, thereafter, cellular selection. There is accumulating evidence that such B cell developmental processes differ with ontogeny, resulting in the generation of distinctive immunoglobulin repertoires at different ages. In mice, ‘B-1’ represents fetal/neonatal B cell development; such development and maintenance appear to depend critically on positive selection, possibly in
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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