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Bcmd Decreases the Life Span of B-2 But Not B-1 Cells in A/WySnJ Mice¹

Vicky M. Lentz^*, Colleen E. Hayes and Michael P. Cancro^2,*

^* Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104; and Department of Biochemistry, University of Wisconsin, Madison, WI 53706

	Abstract

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Peripheral B cells are divided into two subpopulations, B-1 and B-2, the relationship of which remains obscure. We recently showed that the Bcmd mutation in A/WySnJ mice reduces average B cell life span, yielding 90% fewer peripheral B cells. Despite this defect, A/WySnJ mice have an elevated proportion of peritoneal CD5⁺ B cells, suggesting that Bcmd may be the first B-cell-intrinsic gene to differentially affect the B-1 and B-2 subpopulations. To test this hypothesis in detail, we have used in vivo BrdU labeling and four-color cytofluorometry to examine the numbers and turnover rates of sIgM⁺CD23^-CD43⁺ (B-1) and sIgM⁺CD23⁺CD43^- (B-2) splenocytes in A/WySnJ and A/J mice. The results show the expected 90% reduction of splenic B-2 cells among A/WySnJ mice, but a normal splenic B-1 cell pool. Increased B-1 cell renewal cannot explain this undiminished pool, because BrdU labeling kinetics reveals an identical splenic B-1 subset turnover rate of 4%/day in both A/WySnJ and A/J strains. Thus, B-1 cells are Bcmd-independent but B-2 cells are Bcmd-dependent, suggesting Bcmd functions in a positive signaling pathway that imparts longevity to quiescent B cells, but that is not required for cycling B cells. Moreover these results show that the requisites for maturation and longevity differ between the B-1 and B-2 subsets.

	Introduction

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The mechanisms underlying functional and developmental differences between B-1 and B-2 lymphocytes remain unclear (1, 2, 3). The B-2 subset comprises over 95% of adult peripheral B cells, is marrow derived, and develops to steady state numbers of 50 million cells over the first 7 wk of life. In contrast, although B-1 cells predominate in early life, they comprise only 1 to 2% of adult splenic B cells, corresponding to 0.5 to 2.0 million cells. An equal number are found in the peritoneum, where they comprise a larger proportion of the total B cell population, reflecting a paucity of peritoneal B-2 cells. B-1 cells express a restricted specificity repertoire (4, 5, 6, 7, 8), often exhibit autoreactivity (9, 10, 11, 12, 13), and may be associated with some autoimmune diseases (13). Further, B-1 but not B-2 cells exhibit constitutive STAT3 activation (14), consistent with their intrinsic proliferative capacity and self-renewing ability (2).

The origin of B-1 cells, as well as their relationship to the B-2 population, is controversial. B-1 cells may arise from separate progenitors in the fetal liver and neonatal spleen, as has been suggested by developmental patterns, as well as by radiation chimeras reconstituted with marrow vs fetal liver stem cells (2, 15, 16). Alternatively, B-1 cells may be an induced differentiative subset because CD5, a marker often found on B-1 cells, can be induced on marrow-derived cells under certain stimulatory conditions (17).

The A/WySnJ mouse provides a powerful genetic model for studying peripheral B cell development and maturation (18, 19, 20). This strain harbors a single gene defect, Bcmd, that shortens B cell life span, thereby reducing peripheral B cell numbers to only 10% of normal. Previous cytofluorometric analyses suggested that Bcmd does not affect peritoneal CD5⁺ B cells (18). We therefore reasoned that a detailed analysis of how Bcmd affects the B-1 vs B-2 populations might provide insight into the function of Bcmd, as well as the relationship between B-1 and B-2 cells. Here we show that Bcmd shortens the life span of B-2 cells but has no effect on B-1 cells, indicating that these two subsets vary in the differentiation events required for maturation and longevity.

	Materials and Methods

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Mice

The A/J and A/WySnJ mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Experiments used adult male and female mice at 7 to 12 wk of age. All animal husbandry and procedures were done in accordance with the Animal Welfare Act.

Reagents

The following reagents were purchased from PharMingen (San Diego, CA): APC and PE³-labeled anti-CD5 (53–7.3); PE- and biotin-labeled anti-CD23 (IgE FcR) (B3B4); and PE-labeled anti-CD43 (leukosialin) (S7). AMCA-labeled donkey anti-mouse IgM was purchased from Jackson ImmunoResearch, (West Grove, PA). FITC-labeled anti-BrdU (B44) was purchased from Becton Dickinson (San Jose, CA).

Lymphocyte preparation and staining

Cell surface staining was done exactly as described (20, 21). Briefly, cells were preincubated in PBS (50 mM phosphate, 0.15 M NaCl, pH 7.2) containing 0.5% BSA, and then incubated in an optimal amount of fluorochrome-labeled or biotinylated Abs. Three washes preceded all incubations, which were for 30 min on ice. Cells were fixed in PBS containing 1% paraformaldehyde and were analyzed on a Becton Dickinson FACScan using B-D Cellquest software.

Turnover studies

In vivo BrdU labeling was done as previously described (20, 21). The adult A/J and A/WySnJ mice were injected i.p. with 0.6 mg BrdU (Sigma Chemicals, St. Louis, MO) in 0.2 ml of sterile PBS at 12-h intervals for the duration of each experiment. Cells were stained for three or four surface markers (AMCA-, APC-, PE-, and biotin-conjugated Abs followed by streptavidin Red613), washed, and the incorporated BrdU analyzed according to our published procedures (20). Briefly, cells were permeabilized by dropwise addition of ice cold 95% ethanol, washed, and fixed in PBS with 1% paraformaldehyde and 0.05% Tween-20. The cells were then incubated in buffer plus 100 U/ml DNase to partially degrade and denature their chromatin. Finally, the cells were stained with FITC-labeled mAb to BrdU. Cytofluorometric analyses were performed by gating on all nucleated cells.

For each mouse, the percentage of BrdU-labeled cells in each subset (B-1 or B-2) was determined cytometrically and multiplied by the total cell number in the subset to give the number of labeled cells. The means ± SD values were plotted as a function of time, and least squares regression analyses were done on the linear portion of the plot to obtain the BrdU⁺ cell accumulation rate. These linear plots were extrapolated to determine the time to label 50% of cells in the subset. Half-lives were calculated from a first order rate equation assuming a constant pool size during the analysis, as previously described (20). Significance was evaluated using the Student t test.

	Results

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Our previous studies showed that A/WySnJ mice harbor a single, autosomal, codominantly expressed trait, Bcmd, which results in profound B cell deficiency, reflecting severely reduced peripheral life span (18, 19, 20). The results of these studies are summarized in Table I. Surprisingly, when B cells were analyzed from different peripheral compartments, the fraction of A/WySnJ peritoneal B cells that were sIgM⁺CD5⁺ was disproportionately high when compared with A/J (18). Since the previously documented 10-fold reduction in peripheral B cell numbers clearly indicates a substantial effect on the B-2 subset, this observation suggested that Bcmd might differentially affect the B-1 and B-2 subsets. To probe this possibility, we determined the steady state numbers and turnover rates of each population in A/WySnJ and A/J spleens.

The B-1 and B-2 subsets are distinguished by reciprocal patterns of CD23 and CD43 expression (22). We therefore used these markers among sIgM⁺ B cells to compare the splenic B-1 subpopulations of A/J and A/WySnJ mice.

This analysis (Fig. 1) showed that B-1 cells comprised a fourfold larger proportion of A/WySnJ splenocytes than A/J splenocytes. When multiplied by the splenocyte recoveries, these percentages yielded equal numbers of B-1 splenocytes in the two strains (Fig. 2, Table II). In contrast, the B-2 cells comprised a smaller proportion of A/WySnJ splenocytes and, when corrected for cell recoveries, yielded the expected paucity of B-2 cells compared with A/J mice (Fig. 2, Table II).

View larger version (31K): [in this window] [in a new window]   FIGURE 1. Cytofluorometric analysis of B cell subsets in A/J and A/WySnJ mice. Splenocytes from A/WySnJ and A/J mice were stained with AMCA-anti-IgM, PE-anti-CD43, biotin-anti-CD23 (revealed with streptavidin-RED613), and APC-anti-CD5 and analyzed by flow cytometry. Fifty thousand events were collected. A gate (upper panel) was established to include only the sIgM+ cells, and the proportions of B-1 (CD23-CD43+) and B-2 (CD23+CD43-) cells were established (middle panel). Cells falling within the B-1 population (dark box, middle panel) were further analyzed for CD5 (lower panel).

View larger version (10K): [in this window] [in a new window]   FIGURE 2. Numbers of splenic B-1 and B-2 cells among individual A/WySnJ and A/J mice. The number of B-1 and B-2 cells in spleens of individual mice was calculated by multiplying the proportion of each subset by the number of splenocytes recovered for each spleen. Each point is an individual mouse. Bars designate the means.

The normal number of B-1 cells in A/WySnJ mice suggested that Bcmd does not affect B-1 cells. However, adoptively transferred B-1 cells can fully repopulate irradiated hosts, indicating a capacity for self-renewal (23, 24, 25). Therefore, it was possible that Bcmd indeed affects B-1 cells but that compensatory proliferative activity offsets shortened life span, yielding an apparently normal B-1 compartment. To study this point, we measured the BrdU labeling kinetics in splenic B-1 and B-2 cells from A/WySnJ and A/J mice. We reasoned that, if B-1 cells are unaffected by Bcmd, then the labeling rates of B-1 cells in A/WySnJ and A/J should be the same; but if compensatory proliferative activity occurs, then the B-1 population should label faster in A/WySnJ.

The results (Fig. 3, Table II and Table III) showed identical B-1 cell labeling rates and life spans in A/J and A/WySnJ mice. Approximately 4% of the B-1 subpopulation is labeled per day in both strains. This corresponds to 40,000 cells per day and yields a calculated half-life of 17 days. These data indicate that the turnover rate of B-1 cells is similar in the two strains and is sufficient to completely replace the B-1 pool in 3 to 4 weeks.

View larger version (18K): [in this window] [in a new window]   FIGURE 3. BrdU labeling kinetics of splenic B-1 and B-2 subsets in A/J and A/WySnJ mice. Eight-week-old A/J and A/WySnJ mice were given BrdU every 12 h. At the indicated times, splenocytes from three mice per time point were stained individually with AMCA-anti-IgM, PE-anti-CD43, biotin-anti-CD23 (revealed with streptavidin-RED613), and nuclear stained with FITC-anti-BrdU. BrdU incorporation was determined for B-1 (sIgM+CD23-CD43+) and B-2 (sIgM+CD23+CD43-) cells. Upper panels are the numbers and lower panels are proportions of BrdU+ cells among B-1 (left panels) or B-2 (right panels) splenocytes from A/J (open circles) and A/WySnJ mice (closed squares). The mean and SD are shown. Results shown are one of two identical experiments.

This analysis also resolved B cells with the surface phenotype attributed to marginal zone cells, sIgM⁺CD23^-CD43^- (22). These were 60% reduced in number, suggesting they are likely related to B-2 cells (data not shown). In both strains, this population labeled at about 4% per day, presumably reflecting proliferation associated with recent activation (26).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
The results presented herein show that Bcmd, an intrinsic B lineage-specific defect, reduces the life span and pool size of peripheral B-2 cells, but has no effect on peripheral B-1 cells. In conjunction with our previous findings, these observations extend our understanding of the Bcmd mutation, characterize the first B cell-intrinsic mutation that differentially affects B-1 vs B-2 subsets, and provide the first estimate of peripheral B-1 subset turnover rates.

The long-lived mature B-2 cell subset is profoundly affected by Bcmd. In contrast, comparatively short-lived B cell populations, such as the B-1 subset and the immature B-2 compartment, show little or no Bcmd-mediated abnormalities (Ref. 20 and this report). This is most consistent with the suggestion that the Bcmd mutation disrupts a differentiation or life span-lengthening pathway (20). It is inconsistent with the alternative that the mutation disrupts a molecule that dampens a life span-shortening pathway, thereby increasing negative selection. For example, if Bcmd were to decrease the threshold for B cell receptor (BcR)-mediated negative selection, then the short-lived, transitional B cell ought to be most sensitive to the effects of Bcmd, the opposite of what has been observed.

The suggestion that Bcmd disrupts a life span-lengthening pathway in B-2 but not B-1 cells is particularly striking because signaling differences associated with life span determination may indeed exist between these two cell types. Karras et al. (14) recently showed that B-1 cells have constitutively activated STAT3 homodimers whereas in B-2 cells STAT3 must be induced by treatment with IL-6; and Fukada et al. (27) showed that STAT3 mediates anti-apoptotic signals via the IL-6 receptor.

In addition to extending our understanding of the Bcmd mutation, our data reveal a distinction between the B-1 and B-2 subsets that constrains theories of their origins and relationships. The competing models differ regarding how commitment to the B-1 subset occurs. One model suggests that separate precursors exist in the fetal liver but not adult bone marrow (1, 15, 16), and that adult B-1 cells are maintained by self-renewal (27). The alternative model proposes that B-1 cells are the result of B-2 cell activation by TI-2 Ags (17, 28). The data presented here clearly show that B-1 and B-2 cells differ in their requisites for maturation and longevity, since the splenic B-1 cells do not require a normal Bcmd gene product for appropriate life span. Thus, while our data eliminate neither hypothesis, if there are indeed separate lineages, then B-1 cells must utilize other life span-determining mechanisms. Alternatively, if B-1 cells are an activation-induced subset, then early or continuous activation might circumvent the need for a normal Bcmd gene product.

The BrdU labeling studies herein provide the first measurement of splenic B-1 cell turnover. While known to be cycling and self-renewing, their life span and turnover rates were previously undetermined. Here, we show that splenic B-1 cells have a relatively short average half-life (17 days), and their turnover rate is sufficient to replace the entire pool each 3 to 4 wk. Based on this modest production rate, small pool size, and rapid turnover, it is tempting to speculate that a small, extramedullary pool of cells residing in the adult spleen generates B-1 cells at a constant rate throughout adult life. This would be consistent with the rapid achievement of steady state B-1 numbers in early development, as well as with the small proportional representation of B-1 cells in the spleen once a steady-state B-2 population has been established.

Together, these data provide insight regarding the developmental and functional distinctions between B-1 and B-2 cells, and support the possibility that Bcmd disrupts a pathway that imparts longevity to B-2 cells but may be unnecessary in B-1 cells. Additional experiments will be necessary to determine why B-1 cells are Bcmd-independent and to critically assess the role of the Bcmd gene product in B cell development and selection.

	Acknowledgments

 
We thank the Cell Sorting and Flow Cytometry Facility at the University of Pennsylvania for their help with the four- and five-color FACS analysis.

	Footnotes

 
¹ This work was supported by a grant from the Arthritis Foundation (to M.P.C.) and by funds from the University of Wisconsin Department of Biochemistry (to C.E.H.).

² Address correspondence and reprint requests to Dr. Michael P. Cancro, Room 231, John Morgan Building, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104. E-mail address:

³ Abbreviations used in this paper: PE, phycoerythrin; AMCA, aminomethylcoumarin.

Received for publication August 8, 1997. Accepted for publication December 17, 1997.

	References

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