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The Journal of Immunology, 2006, 176: 7159-7164.
Copyright © 2006 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Impaired Transitional B Cell Production and Selection in the Nonobese Diabetic Mouse1

William J. Quinn, III2, Negin Noorchashm2, Jenni E. Crowley, Amy J. Reed, Hooman Noorchashm, Ali Naji3 and Michael P. Cancro3,4

University of Pennsylvania School of Medicine, Philadelphia, PA 19104


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Developing B cells undergo selection at multiple checkpoints to eliminate autoreactive clones. We analyzed B cell kinetics in the NOD mouse to establish whether these checkpoints are intact. Our results show that although bone marrow production is normal in NOD mice, transitional (TR) B cell production collapses at 3 wk of age, reflecting a lack of successful immature B cell migration to the periphery. This yields delayed establishment of the follicular pool and a lack of selection at the TR checkpoint, such that virtually all immature B cells that exit the bone marrow mature without further selection. These findings suggest that compromised TR B cell generation in NOD mice yields relaxed TR selection, affording autoreactive specificities access to mature pools.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
The NOD mouse harbors a multigenic trait yielding autoimmune diabetes (1, 2). Although T lymphocytes are the mediators of pancreatic beta cell destruction, B lymphocytes are also necessary (3, 4, 5, 6, 7, 8, 9), because B cell deficiency or B lineage-specific MHC class II deficiency prevent diabetes in this model. Moreover, the production of insulin-specific autoantibodies often precedes diabetes (10, 11, 12), and NOD mice fail to eliminate transgenic autoreactive B cells (13).

Autoreactive B cells are normally eliminated at one of two checkpoints. The first is in the bone marrow (BM),5 where BCR ligation induces death or receptor editing (14, 15). The second occurs after egress to the periphery, where low avidity self-reactive clones die at the transitional (TR) B cell stage (16). To establish whether these checkpoints operate normally in NOD mice, we have analyzed the development and dynamics of B cell differentiative subsets in the BM and periphery. The results indicate that while BM B cell genesis is normal, peripheral B cell populations are altered, reflecting a collapse of the TR B cell pool at 3 to 5 wk of age. Furthermore, in vivo labeling shows that while few TR cells are generated in NOD mice, virtually all survive to complete maturation. Finally, frequency analysis of {lambda} bearing clonotypes confirms the lack of normal TR selection in the NOD. Together, these findings reveal a B lineage developmental lesion in NOD mice that relaxes selection at the TR checkpoint and likely contributes to the accumulation of autoreactive B cells.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Mice

C57BL/6 and NOD were obtained from Jackson Laboratories or Taconic Farms. All animal procedures were in accordance with the Animal Welfare Act.

Flow cytometric, BrdU labeling, and cell cycle analysis

Lymphocyte suspensions were prepared, and cell surface staining was performed as previously described (17). The rate of continuous in vivo BrdU labeling was assessed as previously described (17).

Cell cycle analyses

Cells were harvested, stained, fixed, and permeabilized; 4',6'-diamidino-2-phenylindole (DAPI) (Molecular Probes) was added at 10 µg/ml and incubated overnight. Cells were analyzed on an LSRII (BD Biosciences) and doublets excluded (18).

Insulitis scores

H&E and Acid Fast stains were performed on pancreata as previously described to identify islets and infiltrating lymphocytes (19).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
The TR B cell pool collapses in juvenile NOD mice

We first assessed the TR, follicular (FO), marginal zone (MZ), and B1 subsets in 8-wk-old NOD and C57BL/6 mice. We consolidated the TR pool using the phenotype B220+, IgM+, CD21/35–, CD43–, because initial results revealed that NOD B cells react poorly with the AA4.1 Ab. The resolution of TR cells with this approach has been reported elsewhere (18) and is verified in Fig. 1A using C57BL/6 mice. Although the proportion of NOD B cells comprised by the FO and B1 subsets differed from controls (Fig. 1B), their numbers were similar (Fig. 1C). In contrast, marked diminution of the TR pool was seen in 8-wk-old NOD mice. In C57BL/6 mice, the TR pool contained ~10 million cells, whereas NOD spleens contained only 1–2 million TR cells (Fig. 1C). In accordance with previous reports (20, 21), the MZ subset in NOD mice was enlarged 3- to 5-fold (Fig. 1C).


Figure 1
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  		FIGURE 1. Splenic B cell subsets in adult NOD and control mice. A, Validation of the phenotyping scheme used to discern the MZ pool (IgMhigh, CD21/35high), FO pool (IgMint, CD21/35int), and to consolidate the TR pool (IgM+, CD21/35low) in young (5 wk old) and adult (10 wk old) C57BL/6 mice. The arrows extending from each cell gate point to histograms displaying AA4.1 expression on each cell population. B, The first column shows total B cells (B220+IgM+); the second column divides this B cell gate into FO cells (IgMint, CD21/35int); MZ and MZ progenitors (IgMhigh, CD21/35high); and an IgM+, CD21/35low gate that is further resolved in the third column into TR (CD43–) and B1 (CD43+CD23–) subsets. C, Numbers for each B cell subset in C57BL/6 (closed); NOD male (open), and NOD female (stippled) were calculated by multiplying the percentages obtained (as in A) by the total number of splenocytes. Bars depict the mean and SD for each subset. In all cases, n ≥ 3. Significance levels are indicated: *, p ≤ 0.05; **, p ≤ 0.01. D, Splenic B cell populations in C57BL/6 (closed) and NOD female (stippled) mice at various ages were analyzed (as in B and C). Bars depict the mean and SD. n ≥ 3 in all cases. E, Insulitis scores were determined as described in Methods for mice at 6, 8, and 10–12 wk of age.

 
To assess the onset of TR and MZ compartment anomalies, we analyzed the establishment of peripheral B cell subsets, simultaneously scoring the mice for insulitis. In NOD mice, peripheral B cell compartments developed normally until 3 wk of age, but by 5 wk of age, they displayed reduced TR cell numbers (Fig. 1D). This was associated with a developmental lag in the FO pool, which failed to reach steady state until 8–10 wk of age. These features were accompanied by a disproportionate enlargement of the MZ pool, consistent with its preferential maintenance in the face of reduced BM output (18, 22, 23). These shifts in NOD peripheral B cell compartments preceded pancreatic islet infiltration (Fig. 1E).

B cell progenitors are normal, but marrow egress is curtailed in NOD mice

Reduced TR B cell numbers, transient FO B cell lymphopenia, and MZ enlargement suggest interrupted B cell production in NOD mice. To determine whether this reflects impaired BM genesis, we assessed BM B cell subsets. In adult NOD mice, the proportions and numbers of pro-, pre-, and immature B cell subsets were normal (Fig. 2, A and B). Thus, reduced TR cell numbers must reflect either failed success at the marrow-periphery interface or more rapid throughput in the TR stages. We analyzed B cell subsets in the peripheral blood (Fig. 2, C and D), reasoning that if BM egress is normal, then blood-borne NOD TR B cell numbers should be comparable to controls. Instead, a 6- to 9-fold reduction in blood-borne TR cells was observed. As expected, the numbers of B1 B cells in NOD blood were consistently similar to controls, whereas the FO populations lagged at 5 wk of age but were similar to controls by 9 wk of age (Fig. 2D).


Figure 2
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  		FIGURE 2. BM and blood-borne B cell subsets in adult NOD and control mice. A, BM was harvested from 8-wk-old NOD or C57BL/6 mice and analyzed. The first column divides B cells into mature recirculating (B220high, IgM+), immature (B220low, IgM+), and B cell progenitors (B220low, IgM–). This IgM– gate is further resolved in the second column into CD43+ pro-B cells and CD43– pre-B cells. B, Absolute cell numbers for each BM B lineage subset in C57BL/6 (closed bars); NOD male (open bars), and NOD female (stippled bars) were calculated by multiplying the percentages obtained by the total number of nucleated BM cells (28 ). Bars show the mean ± SD. In all cases, n ≥ 3. Significance levels are indicated: *, p ≤ 0.05; **, p ≤ 0.01. C, Peripheral blood was harvested from 5-wk-old NOD or C57BL/6 mice and analyzed. The first column divides IgM+, CD21/35low cells from other lymphocytes. This gate is further resolved into CD43+ (B1) and CD43– (TR) B cells in the second column. D, Absolute numbers of blood-borne populations in 5- and 9-wk-old NOD female (stippled bars) and C57BL/6 (closed bars) mice were calculated by multiplying the percentages obtained cytofluorimetrically by the total number of nucleated cells obtained from the blood and adjusted for total blood volume, as estimated by weight. Bars depict the mean and SD for each subset. n ≥ 3 for each strain.

 
TR selection is relaxed in NOD mice

Abnormally low TR B cell production rates in NOD mice would explain lagging FO pool development and transient FO B cell lymphopenia, as well as enhanced MZ recruitment. In addition, because the stringency of TR selection can vary under homeostatic pressure (24, 25), reduced TR production might yield increased throughput and compromised selection at the TR checkpoint. We therefore determined the turnover rates, production rates, and throughput within B lineage subsets using in vivo BrdU labeling. The basis for changes in each population can be precisely interrogated through such analyses, because turnover rates afford an assessment of residency time within each pool, and production rates can identify bottlenecks in generation. Moreover, comparing production rates of progenitor and successor populations estimates throughput, revealing the proportion of cells lost to selection at each checkpoint.

The production and turnover rates of pro-, pre-, and immature B cells in NOD mice were identical with C57BL/6 controls (Fig. 3A), whereas striking deviations were evident in all peripheral subsets (Fig. 3, B and C; Table I). The renewal rate of cells within the TR compartment is substantially slower in NOD mice, indicating that residency time in this pool is doubled. Consistent with a lengthened residency time, we observed a slight enrichment for CD23+ cells in the TR compartment of NOD mice (Fig. 1B and data not shown). Moreover, TR cell production rates are diminished 5-fold, consistent with failures in BM egress. FO and MZ B cells also show slightly reduced turnover rates in NOD mice (p ≤ 0.05).


Figure 3
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  		FIGURE 3. BrdU-labeling kinetics of BM and peripheral B cell subsets in NOD and C57BL/6 mice; 8-wk-old NOD (gray plots) or C57BL/6 (black plots) female mice were treated with BrdU, and their tissues were harvested and analyzed. A, Labeling kinetics of BM subsets are shown. The proportion of BrdU-labeled cells (top panels) was determined cytofluorimetrically, and the absolute number of BrdU-labeled cells (bottom panels) was calculated by multiplying the proportion of labeled cells by the total cells in each subset. Labeling among pro-B, pre-B, and immature B cell subsets are shown in the left, middle, and right plots, respectively. Each point represents an individual mouse. B, Representative histograms of splenic B cell populations from 8-wk-old mice following 3, 5, and 7 days of in vivo BrdU labeling. Labeling among TR, FO, and MZ subsets, gated as in Fig. 1, are shown in the left, middle, and right plots, respectively. C, The proportion of BrdU-labeled cells (top panels) was determined cytofluorimetrically, and the absolute number of BrdU-labeled cells (bottom panels) was calculated by multiplying the proportion of labeled cells by the total number of cells in each subset. Labeling among TR, FO, and MZ subsets are shown in the left, middle, and right plots, respectively. Each point represents an individual mouse. D, {lambda} L chain usage was interrogated using flow cytometry in TR, FO, and MZ subsets. The fraction of {lambda} L chain bearing cells, normalized to the frequency found in the immature BM population of each strain at 5 wk of age, is shown for each subset. Bars show the mean ± SD. In all cases, n ≥ 3. Significance levels are indicated: *, p ≤ 0.05; **, p ≤ 0.01. E, Cell cycle analysis of TR, FO, and MZ subsets in NOD mice was assessed with DAPI staining. BM large pre-B cells were included as the positive control for a cycling population. Doublets were excluded using both forward scatter and DAPI area and height. 

 

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  		Table I. Renewal and production rates in marrow and peripheral B cell subsets of NOD and C57BL/6 micea

 
Lengthened TR residency suggests that the selective criteria applied to these cells are lenient, and assessment of throughput confirms this possibility. Under normal conditions, ~10% of newly formed B cells exit the BM, and fewer than half of these émigrés complete TR differentiation (17), with the rest being lost to specificity-based selection. This pattern is evident in the C57BL/6 controls (Table I). In contrast, production rates of the TR, FO and MZ subsets of NOD mice reveal relaxed selection stringency. First, despite a 5-fold reduction in BM output, the FO production rate is only halved. This indicates that a higher proportion of cells within the TR pool survive to maturity. In fact, the production rate of ~0.3 million FO B cells per day in NOD mice does not differ significantly from the TR production rate, indicating that few, if any, cells are lost to selection at this checkpoint.

We directly interrogated whether clonotypes normally lost during TR selection persist in NOD mice, by analyzing {lambda} L chain usage. Selection against {lambda} bearing clonotypes occurs at both the immature and TR stages (R. Lindsley, M. Thomas, B. Srivastava, and D. Allman, submitted for publication, and Fig. 3D) and, because {lambda} V-gene segment diversity is small, suggests disproportionate specificity-based selection against {lambda} bearing clonotypes. This likely reflects a combination of factors, including residual self-reactivity following exhaustive L chain editing attempts, as well as failed positive selection. NOD B cells display normal reduction in {lambda} frequency between immature and TR stages (Fig. 3D). However, unlike control C57BL/6 mice, no further selection occurs between the TR and FO stages.

Interestingly, the MZ production rate in NOD mice is similar to controls and, when summed with the FO production rate, exceeds the production rate of the TR pool (Table I). Although this might indicate homeostatic proliferation within the FO and MZ pools that compensates for losses incurred after normal TR selection, this was ruled out by cell cycle analyses (Fig. 3E). Accordingly, we favor the suggestion of Srivastava et al. (18) that under lymphopenic conditions most MZ cell genesis proceeds via a FO intermediate, whereas under normal steady-state conditions, the primary route is directly from TR pools. This would cause labeled cells to be tabulated twice in the NOD, once when entering the FO pool and a second time as they pass to the MZ compartment. Furthermore, the frequency of {lambda} usage among MZ B cells is equivalent to the FO compartment in NOD mice but more closely mirrors TR {lambda} frequency in C57BL/6, further strengthening this interpretation.

Impaired BM egress might reflect heightened negative selection in the BM of NOD mice. However, the normal magnitudes and renewal rates of pre-B and immature pools speak against this possibility, as do the similar proportional drops in {lambda} usage between the immature BM and TR compartments of both strains. Thus, we favor the notion that mechanisms associated with either release or transit to the periphery are faulty.

Regardless of the exact mechanism underlying impaired TR B cell production, downstream consequences include indiscriminate passage of TR B cells into mature subsets. Mounting evidence suggests the TR pool is a key checkpoint for B cell selection, since autoreactive and polyreactive specificities are normally eliminated at this stage (26), and their preservation may contribute to autoimmunity (27). Moreover, recent studies show that autoreactive B cells enter the FO and MZ compartments when emerging in a TR environment with little competition (24, 25). Within this context, it is tempting to speculate that impaired TR B cell production relaxes peripheral selection in the NOD mouse, allowing the accumulation of autoreactive clones in mature pools and steadily increasing the likelihood of self-presentation. The NOD model may thus link homeostatic adjustments to transient lymphopenia with relaxed peripheral selection and a heightened probability of autoimmunity (29).


   Acknowledgments
 
We thank Drs. A. Bhandoola and D. Allman for insightful discussion.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by U.S. Public Health Service Grants AI054488 and AG16841 (to M.P.C.) and DK49814 (to A.N.). J.E.C. and H.N. are supported by U.S. Public Health Service Grants AI055428 and DK064603, respectively. Back

2 W.J.Q. and N.N. contributed equally to this work. Back

3 A.N. and M.P.C. share corresponding authorship. Back

4 Address correspondence and reprint requests to Dr. Michael P. Cancro, Professor of Pathology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; E-mail address: cancro{at}mail.med.upenn.edu; or Dr. Ali Naji, Professor of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; E-mail address: alinaji{at}mail.med.upenn.edu Back

5 Abbreviations used in this paper: BM, bone marrow; DAPI, 4',6'-diamidino-2-phenylindole; FO, follicular; MZ, marginal zone; TR, transitional. Back

Received for publication November 21, 2005. Accepted for publication April 21, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

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J. Immunol., March 1, 2007; 178(5): 2996 - 3006.
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