B-1 B cells: development, selection, natural autoantibody and leukemia

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B-1 (CD5+) B cells constitute a phenotypic and functionally distinct population of B cells in mouse that show enriched expression of autoreactive B-cell antigen receptors and that produce several types of natural autoantibodies. Recently, there has been much progress in this field of research. Evidence has appeared for the existence of distinctive B-cell precursors that preferentially generate B-1 B cells, and the crucial requirement for strong B-cell antigen receptor signaling in the maturation of B-1 B cells has been established. Other work focuses on a phenotypically similar population that lacks CD5, termed ‘B-1b’, which shows similarities and differences from most CD5+ B cells in both development and function. The relationship of normal B-1 cells with B-cell lymphomas and leukemias continues to be a subject of interest and debate.

Introduction

B-1 B cells in normal mice show enriched expression of self-reactive B-cell antigen receptors (BCRs) and are responsible for a significant portion of immunoglobulin (Ig)M natural autoantibodies in serum. The majority of B-1 B cells, particularly those that are CD5+, termed ‘B-1a’, are normally produced during fetal/neonatal development. B-1a B cells and a phenotypically similar population that lacks CD5, termed ‘B-1b’, constitute a major fraction of the B cells present in the peritoneal cavity, are a minor fraction of the B cells in spleen, and are rare in lymph nodes (see Table 1 for a comparison of different B-cell populations). In this article I will review recent research with these cells, focusing on issues of development, selection, function and potential relationships to leukemic B cells.

Section snippets

Development of B-1 B cells

The inefficient production of B-1 B cells from precursors in adult bone marrow was noted shortly after their discovery, leading to the proposal that these cells are generated from precursors different from those that develop into typical follicular (termed ‘B-2’) B cells. Later transfer experiments indicated that many of the precursors present in fetal liver produce B-1 B cells, but few B-2 B cells. Yet, the clear dependence of the B-1 phenotype on BCR signaling caused many to discount this

The role of pre-BCR and BCR signaling in B-cell development

B-1 B cell numbers are often more severely impacted than B-2 B cells by mutations that weaken BCR signaling. One of the earliest examples of this is a greatly reduced frequency of B-1 B cells in xid mice that have a mutation in Btk. Btk is a Tek-family intracellular kinase, the activity of which is important for immunoreceptor signaling where it plays a key role in regulating the calcium flux normally induced following BCR signaling. Xid and Btk-deficient B cells fail to show a sustained flux

Antibody production by B-1a and B-1b B cells

Reports regarding novel features of B-1 cells have also emerged in the past several years. The Rothstein laboratory has been investigating the functions of B-1 cells for many years, and has recently found that the pattern of transcription factor expression normally associated with the differentiation of B cells to the plasma cell stage does not hold for Ig-secreting B-1 B cells in the peritoneal cavity [25]. Although BCL-6 and Pax-5 — repressors of the plasma cell gene program — are expressed

Self-antigens selecting B-1 B cells

As mentioned above, the presence of carbohydrate epitopes normally present on the Thy-1 glycoprotein results in the accumulation of B-1 B cells that bear a germline-encoded natural autoantibody BCR and also in the presence of ATA natural autoantibody in serum. The antigens for other natural autoantibodies are not as well defined, but work from the Clarke laboratory [40] indicates that apoptotic cells might serve as the antigen source for certain natural autoantibody specificities. These

B-1 B cells and B-cell leukemia

There is a long-standing issue of the relationship of B-1 B cells with CD5+ B-cell lymphomas and leukemias, both in mouse and in man. B cells were first interrogated for CD5 expression because of its expression on B-cell CLL (B-CLL). Also, the murine CH series of lymphomas isolated by the Haughton laboratory [43, 44, 45] have been shown to utilize a restricted set of BCRs that are commonly found in normal B-1 B cells. Several recent studies describe new mouse model systems that underline this

Conclusions

Shortly after their discovery, two models for the generation of B-1 and B-2 B cells appeared in the literature: development either from distinct precursors or by distinctive activation of a common Ig+ precursor. Both threads of research with B-1 B cells have continued, with work on early developmental distinctions providing evidence for the lineage model and work on signaling requirements for B-1 development providing evidence for the activation model. It seems likely, based on recent work

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

Acknowledgements

I would like to than K Hayakawa for careful reading of this manuscript and for providing helpful comments. This work was done with support from the National Institutes of Health, AI26782 and AI40946.

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