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*
Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several functional criteria support the subdivision of splenic B cells into immature and mature subsets. First, in contrast to mature B cells, immature peripheral B cells do not proliferate upon BCR cross-linking, and instead readily undergo apoptosis in vitro (12, 13). Second, while mature B cells exhibit a cellular half-life of 2–4 mo, as a population immature/transitional B cells turnover rapidly in vivo (1, 2, 4), indicating that the vast majority of these cells either differentiate into mature B cells or die. Immature B cells in the adult spleen can be distinguished from their mature counterparts via their expression of the cell surface phenotype: surface (s) IgM (sIgM)high heat-stable Ag (HSA)highB220low (1, 2), and also selectively express a 130- to 140-kDa protein recognized by the 493 mAb (4).
Recent data suggest that peripheral B cell development is a multistep process. For instance, Loder et al. (3) demonstrated that differential CD23 expression among sIgMhigh splenic B cells reveals two subsets of transitional B cells termed T1 and T2, and suggested that progression of T2 immature B cells into the mature B cells pool is accompanied by a proliferative burst and governed by a BCR-mediated selection event that is partially blocked in xid and CD45-/- mice.
In this report, we characterize subpopulations of sIg+ B cells based on differential surface expression of sIgM, CD23, and the type I transmembrane protein AA4. We find that among sIg+ B cells, AA4 expression is limited to recently formed B cells in the BM and immature/transitional B cells in the spleen. Moreover, in the periphery, simultaneous examination of AA4, CD23, and sIgM expression allows the resolution of three distinct subsets of immature peripheral B cells defined by the surface phenotypes AA4+sIgMhighCD23- (T1), AA4+sIgMhighCD23+ (T2), and AA4+sIgMlowCD23+ (T3); their inability to proliferate following sIgM cross-linking in vitro; and their rapid turnover rate in vivo. We also present a detailed examination of the degree of cellular proliferation within these populations in vivo and the extent to which mutations in the nonreceptor tyrosine kinases btk and lyn impact on the frequencies of each of these compartments. These data, along with our examination of the cellular dynamics of each population in wild-type mice, indicate the existence of multiple selection points without detectable proliferative events within the immature/transitional B cell pool.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Eight- to 12-wk-old female BALB/c mice and BALB.xid (also referred to as C.CBA/N) congenics were bred and maintained in the Institute for Cancer Research animal facility or purchased from Taconic Farms (Germantown, NY). Germfree BALB/c mice were generated and maintained in the Department of Biology at the University of Pennsylvania and were kindly provided by Dr. J. Cebra (University of Pennsylvania, Philadelphia, PA). Lyn-/- mice were kindly provided by Dr. J. Erikson (Wistar Institute, Philadelphia, PA).
Cell preparation and staining
Suspensions of BM cells were flushed from tibias and femurs and splenocytes prepared through perfusion of spleens with FACS buffer (PBS containing 0.5% BSA, 1 mM EDTA, and 0.05% sodium azide). Following lysis of RBCs with 0.165 M NH4Cl2, cells were washed and then incubated with optimal dilutions of the indicated Abs in 96-well round-bottom plates in a final volume of 50 µl. After 30 min on ice, plates were washed twice with FACS buffer and then, when appropriate, cells were incubated for 20 min on ice before two final washes with fluorochrome-conjugated streptavidin (SA) to reveal staining by biotinylated Abs.
Abs and flow cytometric analyses
PE and biotin (BI) anti-CD45R/B220 (RA3-6B2), fluorescein (FL) and BI-anti-CD24/HSA (30F1), and sIgD (AMS 15.1) and allophycocyanin-AA4 (AA4.1) were generated, purified, and conjugated in our laboratories by standard methods. Commercially obtained Abs used in these studies include FL-and BI-conjugated Fab of goat anti-mouse IgM (Jackson ImmunoResearch Laboratories, West Grove, PA) and FL-anti-CD21/CD35 (7G6), I-Ad (39–10-8), CD62L (Mel-14), and CD22 (Lyb-8.2), PE and BI-anti-CD23 (B3B4), and BI-anti-CD138 (syndecan-1; BD PharMingen, San Diego, CA). Biotinylated Abs were revealed with PerCP- or allophycocyanin-Cy7-conjugated SA (BD PharMingen), and dead cells were excluded with propidium iodide. Analyses were conducted on a dual laser flow cytometer (FACSCaliber; BD Immunocytometry Systems, San Jose, CA) or a MoFlo cell sorter (Cytomation, Fort Collins, CA) equipped for detection of nine parameters. All flow cytometry data were analyzed by uploading data files into FlowJo (TreeStar, San Carlos, CA).
Cell sorting
Each indicated B cell subset was isolated on a nine-parameter MoFlo cell sorter (Cytomation) equipped with Summit software and three lasers including an I-90C argon laser tuned to 488 nm and an I-70C Spectrum argon/krypton laser (both from Coherent, Santa Clara, CA) tuned to 647 nm for excitation of allophycocyanin and its derivatives. For experiments examining in vitro proliferation of sorted cells, splenocytes were stained with PE-CD23, BI-B220 (revealed with SA-allophycocyanin-Cy7), allophycocyanin-AA4, and FL-conjugated Fab of goat anti-IgM (µ-chain specific; Jackson ImmunoResearch Laboratories) to avoid BCR cross-linking as a consequence of cell sorting.
In vitro proliferation assays
Sorted cells from the indicated populations were incubated at 30,000–50,000 cells/well in triplicate in 96-well flat-bottom plates in medium consisting of OPTI-MEM, to which was added 5% FCS (Irvine Scientific, Santa Ana, CA), 10 mM glutamine, 10 mM HEPES, 0.5 mg/ml gentamicin, and 5 x 10-5 2-ME. Stimuli added included F(ab')2 goat anti-IgM (µ-chain specific; Jackson ImmunoResearch Laboratories) or LPS (Fisher Scientific, Pittsburgh, PA), both at a final concentration of 50 µg/ml as previously described (2). After 48 h, all cultures were pulsed with 1 µCi of [3H]thymidine and harvested 18 h later for scintillation counting.
Cell cycle analysis
To determine the degree of proliferation in vivo, 50,000 cells from each population were sorted directly into microcentrifuge tubes containing 1 ml of ice-cold 95% ethanol and then stored at -20°C for 24 h. Tubes were then allowed to warm briefly at room temperature before centrifugation and resuspension of cell pellets with PBS containing 1% glucose, 1 mg/ml RNase A, and 50 µg/ml propidium iodide. After a 30-min incubation at room temperature, cells were analyzed on a BD Immunocytometry Systems FACSCaliber utilizing pulse width doublet discrimination.
In vivo 5-bromo-2'-deoxyuridine (BrdU) incorporation
A modification of previously published protocols for assessment of BrdU incorporation was used. Adult BALB/c mice were inoculated with 0.4 mg of BrdU (Sigma-Aldrich, St. Louis, MO) in PBS every 12 h for 0.5–7 days. BM and spleen cells were stained for surface expression of IgM, CD23, and AA4 using standard FACS buffer, washed once with FACS buffer followed by a wash in protein-free PBS, then permeabilized using Fix and Perm (Caltag Laboratories, Burlingame, CA). Subsequently, cells were washed, incubated with DNase I, washed, and then stained with FL-anti-BrdU (BD Biosciences, Mountain View, CA) as previously described (1) before analysis on a BD Immunocytometry Systems FACSCaliber.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous analyses have demonstrated AA4 surface expression on B
lineage progenitors in the BM (16, 17). As shown in Fig. 1
, this includes recently formed
sIgM+sIgD- but not mature
recirculating sIgM+sIgD+ B
cells in adult BM, raising the possibility that AA4 surface expression
is down-regulated after migration of immature B cells into peripheral
lymphoid tissues. Supporting this, only 16–20% of
B220+sIgM+ splenocytes were
AA4+, and these cells were B220low
(Fig. 2). Together, these data suggested that
AA4+B220+sIgM+ cells correspond to
immature/transitional B cells. To test this possibility, we analyzed
AA4 and sIgD expression on BM B220+sIgM+ cells
during the earliest phases of radiation-induced autoreconstitution when
all B cells are phenotypically and functionally immature (2). As shown,
all BM B220+sIgM+ B cells were AA4+
with low to undetectable levels of sIgD 12 days postirradiation (Fig. 1D), indicating that AA4 surface expression correlates with
immaturity.
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, three
subsets of B220+AA4+ cells
in adult spleen can be identified based on differential sIgM and CD23
levels. We designate these populations T1
(sIgMhighCD23-), T2
(sIgMhighCD23+), and T3
(sIgMlowCD23+). Each of
these T subsets constitutes 1–2% of all splenocytes in BALB/c mice
housed in pathogen-free and germfree facilities (Table I).
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, CD24/HSA
levels progressively decrease while sIgD, CD21/CD35, class II, and CD22
levels progressively increase from T1 through T3. Significantly, these
data also show that each AA4+ subset is distinct
from B cells expressing a
CD23-sIgMhigh marginal
zone (MZ) phenotype which express CD21/CD35 and CD22 at levels
comparable to mature B cells, since among AA4+
splenic B cells only the T1 population is CD23-
and these cells express relatively low levels of CD21/CD35 and CD22
(Fig. 3).
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Three subsets of functionally immature peripheral B cells
Assessment of B cell functional maturity can be performed by examining the in vitro proliferative response to BCR cross-linking (2, 20). Whereas mature, follicular B2 cells exhibit a robust proliferative response to this stimulus, immature B cells do not. To verify their functional immaturity, we applied this criterion to sorted subpopulations of B220+AA4+ cells. To preclude inadvertent receptor cross-linking during cell purification, all sIgM staining for functional studies was performed using µ-chain specific, monomeric Fab Abs.
Although
AA4-sIgMlowCD23+
mature B cells readily proliferated following maximal stimulation with
anti-IgM Abs in vitro, we did not detect measurable proliferation
in any of the three AA4+ splenic subsets after
identical stimulation (Fig. 4A). In contrast, all three
transitional populations readily proliferated to LPS (Fig. 4B). Interestingly, levels of LPS-induced proliferation were
consistently lower in T1 cells compared with all downstream
CD23+ populations. Regardless, the inability of
purified AA4+ B cell subsets to proliferate in
response to BCR cross-linking, coupled with their predominance during
the earliest phases of radiation-induced autoreconstitution indicates
that they are functionally immature.
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). The functional immaturity
observed in this population serves to complement assertions based on
cell surface staining and ensure the absence of contaminating mature B
cells in our gating and analysis of this novel subset. Peripheral maturation is not accompanied by a proliferative burst in vivo
Loder et al. (3) previously reported that 17% of
immature CD23+sIgMhigh (T2)
B cells in conventional mice are in the G2-M
phase of the cell cycle, suggesting that peripheral B cell development
is associated with a proliferative burst analogous to surrogate L chain
selection of developing B lineage progenitors in the BM. To quantify
the extent and distribution of basal proliferation within each immature
AA4+ subset, we sorted each population and mature
B cells directly into ethanol, then assessed the DNA content of the
purified cells. Fig. 5 illustrates
representative data from four such experiments. As shown, we were
consistently unable to detect evidence of significant proliferation
within any subset examined, including cells sorted from T2
(AA4+CD23+sIgMhigh).
These data provide unambiguous evidence for the lack of significant
proliferation at each immature stage of peripheral B cell
maturation.
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Although several studies suggest that survival and maturation of immature peripheral B cells can be modulated by negative and positive selection events (3, 12, 13), our ability to subdivide immature splenic B cells into three subpopulations allows us to examine at higher resolution the stage and timing of such events. To probe for evidence of selection events governing transitions in peripheral B cell development, we assessed the cellular dynamics of each population by continuous in vivo BrdU labeling.
A representative BrdU staining profile following 4 days of continuous
BrdU administration for mature B cells and each transitional subset is
illustrated in Fig. 6, and the turnover
rates of BM and splenic immature subsets are depicted in Fig. 7. As shown, each peripheral immature
subset defined by AA4 expression exhibited a rapid rate of turnover
relative to mature AA4- B cells, with cells in
T1 and T2 achieving >90% labeling by days 4 and 5, respectively.
Supporting the notion that CD23+ cells are
derived from less mature CD23- B cells, labeling
kinetics for all AA4+ peripheral B cell subsets
were delayed compared with each immature BM subset, and labeled cells
accumulated in T2 with delayed kinetics compared with those in T1.
Furthermore, cells in T3 also exhibited rapid turnover, albeit with an
even greater delay in labeling kinetics and a reduction in the overall
labeling rate compared with cells in T1 and T2.
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. Interestingly, rates of cell entry
into each population decreased significantly from T1 to T2 and to a
lesser extent from T2 to T3. In contrast, we were unable to detect
evidence for cell loss coincident with movement of cells from T3 to the
mature B cell pool, suggesting that in normal adult mice selection
events resulting from negative or failed positive selection are
restricted to cells within T1 and T2.
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Previous reports have shown that mice possessing mutations of the
Tec family kinase Btk exhibit reduced numbers of mature B cells
(21, 22, 23, 24). Furthermore, other studies have proposed that
the immature B cell compartment of these mice is intact, and have
placed the site of this developmental defect at the transition from
immature to mature B cell (3). However, as shown in Fig. 8, we find that an examination of each
AA4+ B cell subset in xid mice reveals a 10-fold
diminution in the relative and absolute number of T3 phenotype cells,
whereas the T1 and T2 subsets exhibit only 2-fold reductions in total
cellularity (Fig. 8 and Table III).
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In our analysis and as previously reported,
lyn-/- mice possess normal numbers and
ratios of pro-, pre-, and immature B cells in the BM (data not shown)
(26). By contrast, transitional and mature B cell subsets
in the spleen are markedly reduced in number. Moreover, although the
mature B cell compartment is 10- to 20-fold reduced,
AA4+ immature subsets are each reduced 2- to
4-fold (Table III). Importantly, and in direct contrast to the xid
phenotype, we did not detect a selective depletion of any immature
subset in Lyn-deficient mice, indicating that Lyn is likely not
required for specific developmental transitions among immature
peripheral B cells (Fig. 8B and Table III).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Second, all three subsets
clearly lack significant levels of proliferation in vivo (Fig. 5),
indicating that maturation of peripheral transitional B cells is
neither dependent on nor accompanied by entry of developing cells into
the cell cycle. Third, the cellular dynamics of these populations
suggest detectable cell loss within both T1 and T2 or during the
transition of cells in each population into more mature compartments
(Fig. 7B and Table II). Finally, although defects in
peripheral B cell maturation in xid and
lyn-/- mice have been reported
previously, we find that these mutations have markedly different
effects on peripheral B cell maturation, with the xid
mutation effecting a developmental step (T2 to T3) within the immature
B cell pool, and lyn-/- mice exhibiting
normal ratios of each immature subset and highly depressed numbers of
phenotypically mature B cells (Fig. 8 and Table III). Thus, while
previous studies suggested that btk mediates the immature to mature
developmental transition (3), the increased resolution of
these populations afforded herein allows us to conclude that normal btk
function is required for developmental events within the immature
peripheral B cell pool.
Several observations made herein and elsewhere support a developmental
sequence in which cells within T1 give rise to each downstream immature
and mature B cell subset. First, our BrdU-labeling experiments (Figs. 6 and 7), which allow an examination of precursor-product relationships
at steady state in vivo, clearly support this model. Second, newly
formed B cells in the BM are also
CD23- (8), and cells within this
pool become sIgMhigh before migrating to the
periphery (1, 6). Moreover, Carsetti and colleagues
(3) previously demonstrated that
CD23-sIgMhigh B cells
yield CD23+sIgMlow cells
following adoptive transfer. Thus, together these observations support
the notion that
AA4+CD23-sIgMhigh
B cells (T1) give rise to cells in each immature and mature subset
described herein, and thus provide a model for examining the cellular
basis for peripheral B cell development.
In contrast to a previous report (3), we failed to measure significant proliferation in vivo within CD23+sIgMhigh (AA4+) T2 cells. Although the reason for this discrepancy is not immediately apparent, we are confident that isolation of defined subpopulations by electronic cell sorting before DNA content analysis as illustrated herein provides a clear picture of the cell cycle status of any given cell population. Regardless, our data argue against the notion that peripheral B cell development is accompanied by a proliferative burst within T2. Therefore, although btk is clearly required for the efficient development of cells in T2 into T3 and mature B cells, btk may not function to dampen proliferation within T2 as previously suggested (3).
The unique expression of AA4 among splenic B cells also allows a clear
resolution of immature B cells and mature B cells expressing a
so-called MZ phenotype. Indeed, while MZ and T1 B cells are both
CD23-, unlike MZ B cells, cells within T1
clearly express relatively low levels of CD21/CD35 and CD22 (Fig. 3).
Moreover, T1 B cells exhibited unique low levels of LPS-induced
proliferation, and thus differ from MZ B cells which undergo a
hyperproliferative response following LPS stimulation (27
and our unpublished observations).
Several studies indicate that signals mediated through the BCR govern
efficient peripheral B cell maturation. For instance, genetic deletion
of the tryrosine kinase syk blocks peripheral B cell
maturation and entry into B cell follicles (15),
suggesting that syk activity is important for development of
B cells within the immature peripheral B cell pool. Likewise, we find
that btk mediates a developmental step within this compartment as
revealed by the specific reduction of cells within T3 in xid
mice (Fig. 8 and Table III). Together, these findings suggest the
existence of multiple developmental checkpoints during peripheral B
cell maturation. Consistent with this notion, our BrdU studies reveal
appreciable cell loss within both T1 and T2 but not T3 (Fig. 7 and
Table II), suggesting that these mutations might result in pronounced
cellular attrition within T1 and/or T2 rather than during the
transition of immature B cells into the mature long-lived B cell
pool.
Currently the mechanisms underlying the migration of recently formed B cells from the BM to the periphery are unknown. Our findings, along with previous analyses demonstrating AA4 expression on the earliest and all subsequent B cell precursors in adult BM (16, 17), are consistent with the notion that AA4 expression is maintained throughout B cell development until 2–4 days after recently formed sIgM+ B cells enter peripheral lymphoid organs. Given that AA4 bears homology with members of the L-selectin family of homing receptors (28), it is tempting to speculate that AA4 may play a key role in immature B cell egress from the BM and/or entry into peripheral lymphoid tissues.
Rolink et al. (4) reported that immature peripheral B cells selectively express a 130-to 140-kDa cell surface protein identified by the 493 Ab. We suggest that 493 binds to AA4 and cite two lines of evidence in support of this hypothesis. First, both 493 and AA4.1 precipitate a 130- to 140-kDa cell surface protein (4, 28). Second, expression patterns for 493 and AA4.1 are remarkably similar; in the BM both Abs stain all B lineage subsets except for the mature sIgDbright population and in the spleen both Abs stain immature B cells exclusively. Since we have been unable to block AA4.1 staining with 493 supernatant, we further suggest that these Abs recognize noncompeting determinants on the AA4 molecule.
The clear resolution of three immature splenic B cell subsets from other peripheral B cells provides the means to address a number of unresolved issues regarding selection and survival of newly emerging peripheral B cells. For instance, although several studies indicate that self-Ag-mediated negative selection is operative in the BM (6, 7, 8, 9, 10, 11), whether negative selection of immature B cells occurs in vivo in the periphery of conventional mice remains unclear. Likewise, the frequency of receptor editing events in BM vs peripheral immature B cells is also unknown. Recently, Sandel and Monroe (12) provided evidence that receptor editing occurs primarily in the BM, whereas like affinity interactions in immature peripheral B cells result in apoptosis rather than editing. In addition, Yu et al. (29) recently proposed that germinal center B cells exhibiting evidence for receptor editing are derived solely from immature peripheral B cells. Although consistent with data demonstrating that immature peripheral B cells are receptive to CD40-CD40L ligand-mediated interactions required for formation of germinal centers (4), these experiments raise questions regarding the overall and relative contribution of each immature B cell subset to the germinal center reaction and the generation of the memory B cell pool.
Finally, understanding the mechanisms underlying the development, selection, and migration of recently formed B cells as well as mechanisms controlling life span and migration of mature B cells will require the clear identification of each relevant B cell subpopulation. AA4, in conjunction with varying levels of sIgM, CD21, and CD23 expression, readily allow the resolution of these populations and should thus aid in future experiments designed to address these issues.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. David Allman, Biomedical Research Building II, III, 421 Curie Boulevard, Room 553, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160. E-mail address: dallman{at}mail.med.upenn.edu
3 Abbreviations used in this paper: BCR, B cell receptor; BM, bone marrow; s, surface; HSA, heat-stable Ag; SA, streptavidin; BI, biotin; FL, fluorescein; BrdU, 5-bromo-2'-deoxyuridine; T, transitional; MZ, marginal zone.
Received for publication August 16, 2001. Accepted for publication October 12, 2001.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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