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The Journal of Immunology, 2001, 166: 2163-2166.
Copyright © 2001 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge Commentary: Origins of B-1 Cells1 ,2

Henry H. Wortis3 and Robert Berland

Department of Pathology, Tufts University School of Medicine and Program in Immunology, Sackler School of Graduate Biomedical Sciences, Boston MA 02111


   Abstract
Top
 Abstract
Introduction
 References
 
The origin of B-1a cells, a minority population of B cells that express CD5, are abundant in coelomic cavities, and often produce autoantibodies, has been the subject of study for many years. Accumulating evidence demonstrates that the hypothesis that only B cells arising in fetal or neonatal tissues have the potential to become B-1a cells cannot be true. Rather, B cell receptor-mediated signaling initiated by ligation of autoantigen has now been shown to be required for induction of the B-1a phenotype. Furthermore, cells with a functional B-1a phenotype can be induced from adult precursors by appropriate Ag. At the same time, microenvironment-specific events may determine the likelihood that a given B cell, either adult or fetal derived, enters this pathway. CD5 expression and possibly localization to the peritoneum appear to provide some protection to autoreactive cells otherwise slated for elimination.


   Introduction
Top
 Abstract
 Introduction
References
 
For many years there has been an intellectual argument as to the origin of B-1 cells, that small population of B cells characterized by a unique functional and surface phenotype. Best described in the mouse, B-1a cells express CD5, CD43, high membrane IgM (mIgM),4 low mIgD, low or no CD23, and low CD45(B220). B-1a cells in the peritoneal cavity (PerC), where they are found in abundance, also express CD11b. These cells frequently produce Abs that are encoded by germline unmutated Ig genes, often reacting with bacterial carbohydrate Ags and/or autoantigens. And, unlike the B-2 cohort, B-1 cells are long lived in vivo and in vitro (reviewed in Refs. 1 and 2).

Although B-1 cells are relatively infrequent in the spleens of adult mice of most strains, they are a significant portion of the fetal and neonatal splenic B cell population (3). They are also generated in relatively high frequency from transferred fetal precursors and infrequently (4, 5), or perhaps never (6), from adult bone marrow. These findings led to the hypothesis that B-1a cells are generated exclusively from fetal precursors while adult bone marrow only produces B-2 cells. This is the committed precursor hypothesis.

On the other hand, in vitro experiments indicated that at least some of the surface characteristics of B-1a cells could be generated by stimulation of splenic B cells with anti-IgM (7). This suggested the possibility that any B cell would acquire a B-1a phenotype if an Ag caused multivalent mIgM cross-linking. That is, stimulation by T-independent type 2 Ags such as bacterial carbohydrates and autoantigens such as DNA induce splenic follicular B-2 (also known as B-0) cells to differentiate into B-1a cells. Differences in the repertoires of fetal and adult precursors resulting from the lack of expression of TdT in fetal tissue and the preferential usage of 3' VH genes by fetal pre-B cells were proposed to explain the high production of B-1a cells from fetal sources (8).

In the years since the posing of these alternative hypotheses, experimental evidence from several laboratories has imposed limitations on the simplest forms of these theoretical alternatives. Now, in the last year and a half, independent studies from a variety of laboratories, the most recent published in this issue of The Journal of Immunology, have fundamentally shifted the grounds of the debate.

The first evidence from animal-based experimentation that challenged the lineage hypothesis was a study by Clarke and colleagues (9) of mice expressing transgenes encoding the heavy (VH12) and light (V{kappa}4) chains of an anti-phosphatidylcholine (anti-PtC) Ig that is typically found in B-1a cells . These transgenic mice produced high numbers of transgene-expressing B-1a cells in the spleen and the peritoneum. In contrast, mice with B cells expressing transgenes encoding typical splenic B-2 Abs generate B cells with a B-2 phenotype (cf Refs. 10, 11, 12). Although these results could be interpreted as showing that specificity (repertoire) is sufficient to determine phenotype, it was not shown that any of the mature B cells originated from adult bone marrow rather than fetal sources.

Accumulating evidence from many laboratories shows that whatever their origins, B-1 cells are not produced when signals through the B cell receptor (BCR) are attenuated. Thus, naturally occurring or deletional mutations of a variety of BCR signal transducers or costimulating molecules both compromise BCR signaling and prevent or significantly diminish the generation of B-1a cells (see Table IGo). Conversely, loss of negative regulation increases the numbers of B-1a cells (see Table IGo). That B-1a cell development is contingent on BCR signaling is easily accommodated by the lineage hypothesis if potential B-1a cells need to be positively selected by (auto) Ag (cf Ref. 2).


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  		Table I. Genetic events that alter the number of B-1a cells

 
The necessity for an interaction with autoantigen to generate B-1a cells of at least one specificity was demonstrated by a collaborative study from the laboratories of Hayakawa and Hardy (13). They created transgenic mice that expressed the heavy chain SM6C10. This heavy chain was originally identified in a B-1a-derived hybridoma that produces Ab to the T cell surface Ag Thy-1. SM6C10 expressing B cells with a B-1a phenotype were found in transgenic mice with a normal genetic background. However, when the transgene was bred so as to create mice with a deletional mutation of thy-1, SM6C10 expressing B-1a cells were not detected. Therefore, autoantigen is necessary for the production of (SM6C10-expressing) B-1a cells with specificity for the autoantigen Thy-1.

That CD5 is expressed on these autoantibody-producing cells is one of many intriguing and seemingly idiosyncratic features of B-1a cells. Insight into this correlation comes from a study by Hippen et al. (14) which demonstrates that CD5 expressed on B cells plays a role in maintaining tolerance to autoantigens. They reexamined the anergic B cells that arise in mice doubly transgenic for anti-hen egg lysozyme (HEL) and soluble HEL (sHEL) and showed that these cells expressed CD5 at a level significantly higher than the small amount seen on B-2 cells (15) but less than that found on B-1a cells. This is intriguing, in part because anti-HEL is an Ab typical of the adult repertoire, but also because it suggests that CD5 might play a role in maintaining B cell tolerance. That this is so was shown when the anti-HEL and sHEL transgenes were bred onto a CD5-/- background. Unlike all CD5+ mice, several CD5-/- animals broke tolerance and produced anti-HEL Abs. This supports evidence from in vitro studies of CD5-/- mice that CD5 acts as a negative regulator of signaling through the BCR of B-1 cells (16).

In the experiments reported elsewhere in this issue, Clarke and collaborators (17) examine the ability of splenic B cells with a B-2 phenotype to differentiate into B-1a cells in vivo. The test system is yet another Ig transgene model, this time with a transgene encoding the heavy chain 2-12H. This heavy chain was derived from a cell producing Ab that reacts with the autoantigens ssDNA and the ribonucleoprotein (RNP) Sm. This gene was originally expressed in a hybridoma derived from an autoimmune disease-prone MRL/lpr mouse. In adult mice, transgene-expressing cells with a B-1a phenotype were found in the peritoneum while B-2 cells with a transitional (not fully mature) phenotype were seen in the spleen. When the splenic B-2 cells were transferred to lightly irradiated nontransgenic littermates, they could be recovered from the spleen as transitional B-2 cells or in the peritoneum as B-1a cells. This demonstrates that whatever the origin of their progenitors, B-1a cells can first reside in the spleen with a CD5- surface phenotype similar to, if not identical with, that of B-2 cells. In other words, splenic B-2 cells can give rise to peritoneal B-1a cells.

Because many of the splenic transitional B-2 cells have a short life (unlike B-1a cells), the authors propose that differentiation into long-lived peritoneal B-1 cells is a mechanism that preserves tolerant autoreactive cells. In this regard, these studies provide independent support for the idea that CD5 expression and other elements of the B-1 phenotype might serve to safely maintain cells that are autoreactive and therefore potentially harmful.

In an earlier study, the Clarke group (18) showed that 2-12H transgenic mice had low spontaneous levels of anti-Sm Ab but responded to immunization with small nuclear RNPs (snRNPs) plus CFA with a greater than 6-fold induction in serum anti-Sm. Thus, anti-Sm B cells can be activated under the appropriate circumstances in these mice.

One possibility is that the B-1 phenotype (in particular the expression of CD5) may necessitate stronger signaling through the BCR to achieve activation and that the levels of snRNPs present in the PerC are insufficient for activation. Consistent with this, Qian et al. (17) now show that expression of the 2-12H transgene in conjunction with either CD19 overexpression or CD22 deletion results in elevated serum anti-Sm. Since CD19 is a positive and CD22 a negative regulator of BCR signaling, both perturbations lower BCR signaling thresholds, perhaps by this means allowing activation of Sm-specific B cells by the snRNP present in the absence of immunization.

Qian et al. (17) also show that in the absence of CD19, transgene-expressing B-1a cells fail to accumulate in the peritoneum. This could be because binding of an Ag-C3 complex to mIgM plus the CD19-CD21-CD81 complex, in contrast to Ag binding to mIgM alone, provokes a signal strong enough to induce B-1a development (19). Alternatively, CD19 might provide a qualitatively different signal that is minimally required for B-1a survival (20).

There may well be an adaptive advantage to this risky chain of events that allows autoreactive cells to exist and prosper. This is indicated by the observation that both B-1a- and B-2-derived Abs are necessary for effective responses to some pathogens (21).

The studies with Ig-transgenic mice discussed so far demonstrated the importance of Ig specificity in B-1a development. Arnold et al. (22) and Qian et al. (17) show in two different transgenic models that adult splenic B cells expressing a B-1 specificity but with either a transitional B cell surface phenotype (17) or a surface phenotype intermediate between B-1a and B-2 (22) can subsequently develop a (full) B-1a surface phenotype. This suggests that adult B cells with an appropriate specificity can differentiate into B-1a cells and argues against the idea of a unique, fetal-derived B-1a lineage.

However, these experiments did not unambiguously rule out a fetal origin for the observed splenic B-1a precursors. Moreover, in none of these transgenic models was it demonstrated that B-1a cells that develop have any functional properties of normal B-1a cells. Both of these issues were addressed in a Journal of Immunology article by Chumley et al. (23) that appeared early in 2000. These studies involved mice transgenic for another B-1a-derived anti-PtC Ab, this time incorporating the heavy/light chain combination VH11/V{kappa}9. They found that transferred CD445(B220)-/CD19- bone marrow cells from adult mice gave rise to B-1a cells. Furthermore, transgene-expressing B cells expanded in vitro from IL-7-cultured bone marrow developed a B-1a phenotype. B-1a cells did not develop, either in vivo after adoptive transfer or in vitro after culture in IL-7, when the source of bone marrow was mice expressing the 3-83 transgene, an Ab normally expressed on splenic B-2 cells. Both in vitro- and in vivo-generated VH11/V{kappa}9-transgenic B-1a cells exhibited the prolonged longevity in vitro that is a property of normal B-1a cells. In summary, B-1a cells can, in fact, derive from adult progenitors provided they express the appropriate Ag specificity.

Other recent experiments highlight similarities between peritoneal B-1a cells and splenic marginal zone (MZ) B cells (reviewed in Ref. 24). Both are mIgM high, mIgDlow, CD23-, and CD43+. Unlike B-1a cells, MZ cells are typically CD5-, CD1+, and CD21high. Neither population proliferates in response to BCR cross-linking. MZ cells produce Ab in response to the TI-2 Ag TNP-Ficoll (25) while TI-2 responses to 1,3 dextran (26) and the phosphorylcholine (PC) Ag of Streptococcus pneumoniae require B-1a cells (27, 28).

Like B-1a cells, MZ B cells are selected into a particular microenvironment by a process that is at least partially repertoire and ligand dependent as expression of the heavy chain transgenes VH81X or M167 drives B cells into MZs (29). Furthermore, examination of mice transgenic for genes generating Abs with different affinities for the bacterial Ag PC reveals that cells with the highest affinity for PC are found as peritoneal B-1a cells while those with a lower affinity appear as MZ cells (30).

Yet, distinctions between B-1a and MZ cells remain sharp. Thus, although the ability of mice to generate MZ B cells is lost when the gene for the proline-rich tyrosine kinase-2 (PYK-2/RAFTK) is deleted by mutation, the B-1a population remains intact (25). Cell transfer studies were consistent with the idea that it is the expression of PYK-2 in B cells rather than in cells of the microenvironment that is critical for MZ development. Although much work remains to be done to understand MZ and B-1a cells, it is possible that they share features of a common activation pathway, but differ with respect to the receptors they express and their response to putative ligands of their respective local environments.

Collectively, studies on the genesis of B cells lend strong support to the notion that, as the late Geoffrey Haughton put it, "B-1a cells are made, not born" (31). Although this new evidence does provide compelling support against the simplest form of the fetal origin:B-1a destiny concept, it is still very possible that differences between fetal and adult B cell development can play a role in determining the ultimate phenotype of a developing B cell.

First, unlike adult progenitor B cells, fetal cells do not express TdT (32) and therefore their rearranged Ig genes lack N insertions. In addition, there are well-established differences between V region usage in fetal and adult development with fetal-derived B cells displaying preferential use of 3'-V regions (33). This could be due to differences in frequencies of rearrangement, differences in postrearrangement selection (34), or both; with current evidence favoring differences in selection at the pre-B cell stage as the predominant mechanism. Present evidence does not rule out that repertoire differences are due entirely to the presence or absence of N additions plus different postselection outcomes due to the availability of selecting ligands or to differences in the response of fetal vs adult pre-B cells to similar ligands. However, other differences between fetal and adult B cell development have been reported (e.g., Ref. 35).

Second, studies of T cell maturation have shown that at several critical choice points ({gamma}/{delta}, CD4/CD8) the strength of signal through the TCR can determine cell fate. Yet at the same time, ligation of Notch to extracellular ligands can also influence cell fate (reviewed in Ref. 36). Quite recently it was shown that Notch influences B/T fate decisions (37). It is conceivable that a similar mechanism influences fate decisions for developing B cells. It would not be unreasonable to speculate that the fate of a given B cell might depend on both the strength of the affinity of its receptor for autoantigen and the availability of ligands in the microenvironment for Notch or a Notch analogue expressed on progenitors.


   Footnotes
 
1 This work was supported in part by National Institutes of Health Grant AI15803. Back

2 This article is dedicated to the late Geoff Haughton, whose infectious humor and love for intellectual debate brought out the best in us. Back

3 Address correspondence and reprint requests to Dr. Henry H. Wortis, Department of Pathology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111. Back

4 Abbreviations used in this paper mIgM, membrane IgM; PerC, peritoneal cavity; BCR, B cell receptor; HEL, hen egg lysozyme; sHEL, soluble HEL; RNP, ribonucleoprotein; snRNP, small nuclear RNP; MZ, marginal zone; PC, phosphorylcholine; PtC, phosphatidylcholine. Back

Received for publication December 13, 2000. Accepted for publication December 20, 2000.


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