Review
Development and function of B-1 cells: Commentary

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Abstract

Results from immunoglobulin-transgenic mice and BCR-mutant mice have been widely interpreted in recent years as supporting a simple ‘activation’ model for the origin of CD5+/B-1 B cells. However cell transfer experiments over 10 years ago and recent work investigating pre-BCR signaling suggest striking differences between B cell development in fetal liver and adult bone marrow, lending support for a ‘lineage’ model that we favor. Recent progress has been made relating to the development and function of the CD5+/B-1 B cell subpopulation in mice; the data can be viewed in the context of the generation of this subpopulation by a distinctive fetal B cell developmental process.

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

References (59)

  • G.H. Kline et al.

    Pre-B cell receptor-mediated selection of pre-B cells synthesizing functional mu heavy chains

    J Immunol

    (1998)
  • E. ten Boekel et al.

    Changes in the V(H) gene repertoire of developing precursor B lymphocytes in mouse bone marrow mediated by the pre-B cell receptor

    Immunity

    (1997)
  • C. Tatu et al.

    Selection at multiple checkpoints focuses V(H)12 B cell differentiation toward a single B-1 cell specificity

    J Exp Med

    (1999)
  • K.P. Lam et al.

    B cell antigen receptor specificity and surface density together determine B-1 versus B-2 cell development

    J Exp Med

    (1999)
  • M. Gui et al.

    Peripheral CD4+ T cell maturation recognized by increased expression of Thy-1/CD90 bearing the 6C10 carbohydrate epitope

    J Immunol

    (1999)
  • K. Hayakawa et al.

    Positive selection of natural autoreactive B cells

    Science

    (1999)
  • S.H. Clarke et al.

    B-1 cell development: evidence for an uncommitted immunoglobulin (Ig)M+ B cell precursor in B-1 cell differentiation

    J Exp Med

    (1998)
  • T. Litzenburger et al.

    B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice

    J Exp Med

    (1998)
  • X.F. Qin et al.

    Secondary V(D)J recombination in B-1 cells

    Nature

    (1999)
  • M.C. Carroll

    The role of complement and complement receptors in induction and regulation of immunity

    Annu Rev Immunol

    (1998)
  • H. Suzuki et al.

    Xid-like immunodeficiency in mice with disruption of the p85 alpha subunit of phosphoinositide 3-kinase

    Science

    (1999)
  • D.A. Fruman et al.

    Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85 alpha

    Science

    (1999)
  • G. Sen et al.

    Negative regulation of antigen receptor-mediated signaling by constitutive asociation of CD5 with the SHP-1 protein tyrosine phosphatase in B-1 B cells

    Eur J Immunol

    (1999)
  • J.J. Perez-Villar et al.

    CD5 negatively regulates the T-cell antigen receptor signal transduction pathway: involvement of SH2-containing phosphotyrosine phosphatase SHP-1

    Mol Cell Biol

    (1999)
  • H. Nishimura et al.

    Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses

    Int Immunol

    (1998)
  • H. Takeshita et al.

    Abrogation of autoimmune disease in Lyn-deficient mice by the mutation of the Btk gene

    Int Immunol

    (1998)
  • J. Calvo et al.

    Relevance of individual CD5 extracellular domains on antibody recognition, glycosylation and co-mitogenic signalling

    Tissue Antigens

    (1999)
  • M.S. McAlister et al.

    Structural analysis of the CD5 antigen — expression, disulphide bond analysis and physical characterisation of CD5 scavenger receptor superfamily domain 1

    Eur J Biochem

    (1998)
  • P.M. Rudd et al.

    Oligosaccharide analysis and molecular modeling of soluble forms of glycoproteins belonging to the Ly-6, scavenger receptor, and immunoglobulin superfamilies expressed in Chinese hamster ovary cells

    Glycobiology

    (1999)
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