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Original Article |
honjo{at}mfour.med.kyoto-u.ac.jp
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Key Words: transgenic lines • homozygosity • flow cytometry • anti-RBC antibody
Productive VHDHJH recombination in the Ig H chain locus of one allele of the B cell results in suppression of VHDHJH recombination in the other allele. Thus, a B cell expresses generally only one H chain gene out of two alleles 1. This phenomenon is called H chain allelic exclusion. Surface expression of the µ chain has a critical role in allelic exclusion of the H chain locus because targeted disruption of the µ chain membrane exon results in loss of H chain allelic exclusion 2. The essential role of the cell surface µ chain expression in allelic exclusion is also supported by studies using Ig transgenic (Tg)1 mice 3. Mice expressing the membrane-form µ chain transgene inhibit expression of the endogenous µ chain, whereas Tg mice with the secreted form µ chain do not show such inhibition 456. In addition, expression of Ig L chain transgenes also exerts suppression on the rearrangement and expression of the endogenous L chain Ig locus 67. However, the suppression of endogenous H and L chain gene expression in Ig Tg mice are generally not complete, and efficiencies of the suppression are variable among different lines of Tg mice 891011121314151617. Variable integration sites of transgenes may influence the onset and level of transgene expression, which may affect the efficiency of allelic exclusion. Since the V(D)J recombination event in each B cell is all or none, it has not been clear whether allelic exclusion can be induced by a small number of surface µ chain or if it requires a relatively higher number of surface µ chain (a threshold). To examine these possibilities, quantitative comparison between the levels of transgene expression and suppression of endogenous H and L chain gene expression should be carried out using Tg lines with the same integration site to avoid the difference due to the developmental onset of transgene expression.
We have generated Tg mice that produce an autoantibody (4C8) to RBCs, and have analyzed the mechanisms of B cell tolerance and B-1 cell activation 18192021222324. Since autoreactive B cells are eliminated at the immature stage in the bone marrow, the number of self-reactive B cells is markedly decreased in the bone marrow, peripheral blood, spleen, and lymph nodes in the Tg mice. In contrast, the peritoneal cavities of the Tg mice contain a normal number of autoreactive B-1 cells that can be eliminated by interaction with RBCs 1819. B-1 cells show distinct surface antigen expression and anatomical localization from conventional B (B-2) cells 25262728. Furthermore, the VH gene usage, N region diversity, and antigen specificity of B-1 cells are also unique 293031323334. B-1 cells are thought to be generated from fetal liver cells, and two independent studies have demonstrated that adult bone marrow cells do not give rise to CD5+ B-1 cells after transfer to irradiated hosts 3536. In contrast, Wortis and colleagues 373839 have shown that adult bone marrow contains precursors for CD5+ cells and that CD5 expression in splenic B cells is induced by surface IgM cross-linking, suggesting that B-1 cells are generated from common precursors to conventional B cells. Arnold, Clarke, and colleagues 4041 have reported that B-1 cells differentiate from B-0 cells after expression of specific antigen receptors. Thus, it is not yet clear whether B-1 cells constitute a B cell lineage distinct from conventional B cells. In addition, even if some B-1 cells are derived from activation of B-2 cells, it is not clear whether a certain threshold level of B cell receptor (BCR) expression is required for B-1 cell differentiation or if the receptor specificity alone plays a major role.
To answer these questions we generated new lines of anti-RBC antibody Tg mice that carried tandem joined H and L chain (H+L) transgenes, and we compared the levels of allelic exclusion and the size of B-1 cell compartment between homozygotes and heterozygotes that differ only in the level of the surface Ig expression. Suppression of endogenous H and L chain gene expression was more prominent in homozygotes than in heterozygotes, suggesting that allelic exclusion depends on a certain level of surface Ig expression. In addition, the size of the Tg B-1 cell compartment in the peritoneal cavity is larger in homozygous than in heterozygous H+L mice, suggesting that the increase in the B-1 cell compartment in the Tg mice may be due to augmentation of signals through surface Ig by the self-antigen (RBC).
Materials and Methods
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Materials and Methods
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Tg Mice.
Tg mouse lines carrying either H or L chain gene for the anti-RBC mAb (4C8 mAb) have been established previously 18. Double Tg (HxL) mice with H and L chain transgenes were obtained by mating H and L chain Tg mice. In this study we generated new lines of 4C8 mAb Tg mice that carried tandem joined H and L chain transgenes. To construct tandem joined transgenes, a 5.6-kb BamHI fragment of pMO-
4C8 was first subcloned in the BamHI site of pSP73 Vector (Promega Corp.). Next, a 15.5-kb XhoI fragment of pMO-µ4C8 was subcloned between the SalI and XhoI sites. The pSP73 plasmid containing both H and L chain genes was designated as pSP73-µ4C8. Tandem joined H and L chain Tg (H+L) mice were generated by injecting a 22.0-kb PvuI–XhoI fragment of pSP73-µ4C8 (see Fig. 1 A). Heterozygous mice were mated to get homozygous mice in two representative lines, H+L5, with 4–12 copies, and H+L6, with 1–3 copies of the transgene. The presence of the transgenes and homozygosity of the Tg loci were screened by PCR and Southern blot analysis. Tg mice were maintained under conventional conditions in our animal facility.
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Immunological Reagents.
FITC- or Cy-Chrome®–conjugated anti–mouse CD45R (B220), FITC- or PE-conjugated anti–mouse IgMa (Igh-6a), FITC- or PE-conjugated anti–mouse IgMb (Igh-6b), PE-conjugated anti–mouse CD11b (Mac-1 
chain), biotin-conjugated anti–mouse 
1 and 2 L chain mAbs, and FITC- or Cy-Chrome®–conjugated streptavidin (SA) were purchased from PharMingen. FITC- or biotin-conjugated F(ab')2 fragments of goat anti–mouse IgM were from ICN Pharmaceuticals (Cappel). PE-conjugated SA was from Dako. Anti-idiotype (Id) mAb (S54) against the transgene-encoded anti-RBC antibody (4C8) 18 was conjugated with N-hydroxysuccinimidobiotin (Pierce Chemical Co.) according to the directions provided by the manufacturer.
Flow Cytometric Analysis.
Single cell suspension from bone marrow was prepared by flashing femur bones with a staining buffer (PBS containing 2% FCS and 0.05% sodium azide), gently pipetted, and washed with the staining buffer. Single cell suspensions from bone marrow, spleen, and peritoneal cavity were prepared with the staining buffer and pretreated with 10% heat-inactivated normal rat serum. After 15 min of incubation, FITC- and/or biotin-conjugated mAbs at appropriate dilutions in the staining buffer were added directly. After 30 min of incubation, PE-conjugated mAbs and/or FITC- or PE-conjugated SA was added. Before and after each step of incubation, cells were washed with the staining buffer. Stained cells were then applied to FACSCalibur® (Becton Dickinson). After excluding dead cells by propidium iodide staining, cells present in the lymphocyte gate defined by forward and side light scatters were analyzed.
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Inhibition of Endogenous H Chain Expression Is Stronger in Homozygous than in Heterozygous Mice.
To test whether inhibition of endogenous H chain expression is stronger in homozygous than in heterozygous mice, we analyzed lymphocytes in bone marrow and spleen of H+L5, H+L6, and H3 mice by flow cytometry. We stained bone marrow and spleen cells with antiallotypic mAbs (which can clearly distinguish IgM of the control mice; Fig. 2A and Fig. B) for IgMa (Tg) and IgMb (endogenous). In all heterozygous Tg mice, the numbers of IgMa+IgMb+ cells (allelic inclusion) were small but significant, whereas these cells almost completely disappeared in all homozygous Tg mice. This conclusion is further confirmed by the finding that both bone marrow and spleen B cells with only endogenous H chains (IgMa–IgMb+) decreased in homozygous Tg mice as compared with heterozygous Tg mice (Fig. 2A and Fig. B). In all lines of Tg mice, total numbers of endogenous H chain–expressing (IgMb+) spleen cells were lower in homozygous than in heterozygous mice (Fig. 2 C). These results indicate that inhibition of endogenous H chain expression (allelic exclusion) is stronger in homozygous than in heterozygous mice. Taken together, higher levels of Ig transgene expression appear to cause stronger inhibition of endogenous H chain expression, suggesting that a certain level of surface Ig expression is required for allelic exclusion of the H chain locus.
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chain is not known, we estimated the degree of endogenous L chain expression by difference in expression of Tg H chain (IgMa) and Id (the combined epitope of the H and L chains of the 4C8 anti-RBC mAb) that is recognized by the S54 mAb. In the H+L5 line, two populations of IgMa+ cells were observed: one stained with both anti-IgMa and anti-Id mAbs diagonally, and the other stained more weakly with anti-Id mAb than with anti-IgMa mAb (Fig. 3a, Fig. B, and Fig. D, tops). As a control, IgMa+ cells from H3 mice did not contain the population stained with the S54 mAb (Fig. 3B and Fig. D, bottoms). We presume that the cells that stained diagonally with both mAbs express the Tg H and L chains equally, and that the IgMa+Idlow cells express the Tg H chain with both endogenous and Tg L chains. In support of this assumption, IgMa+ bone marrow cells in heterozygous H+L6 mice, which consisted of almost exclusively IgMa+Id+ cells and only few IgMa+Idlow cells, contained <1.2% + cells, which represent a fraction of B cells that express endogenous L chains (Fig. 3 A). In contrast, IgMa+ bone marrow cells in heterozygous H+L5 mice, which consisted of 
28% IgMa+Id+ and 72% IgMa+Idlow cells, contained >5.5% + cells (Fig. 3 A). Furthermore, IgMa+ spleen cells in heterozygous H+L5 mice, which consisted of 4% IgMa+Id+ and 96% IgMa+Idlow cells, contained >14% + cells (Fig. 3 A). The total number of cells expressing endogenous L chains (IgMa+Idlow) in bone marrow (Fig. 3B and Fig. C) and spleen (Fig. 3D and Fig. E) was less in homozygous than in heterozygous Tg lines, indicating that homozygosity of the Tg loci enhances the inhibition of endogenous L chain expression as compared with heterozygosity.
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Several lines of evidence suggest that surface expression of the µ chain is critical for H chain allelic exclusion 2456. In addition, pre-BCR, which is the H chain paired with the surrogate L chain, is suggested to mediate H chain allelic exclusion through downregulation of recombination-activating genes 4243444546. Ig and Igβ, which associate with surface-expressed H chains, have also been shown to trigger the signals inducing allelic exclusion 474849. Taken together, expression of the H chain as a pre-BCR on the cell surface may induce signals mediated by Ig and Igβ, resulting in H chain allelic exclusion. In this study we have demonstrated that homozygosity of the transgene Ig loci increases surface Ig expression on bone marrow B cells and causes stronger allelic exclusion, as compared with heterozygosity. Since allelic exclusion is all or none in each B cell, the present results suggest that there is a threshold of the pre-BCR signal intensity that induces allelic exclusion.
There are several other possibilities to explain our results. First, B cells with allelic inclusion may be negatively selected. However, Sonoda and Rajewsky 50 have shown that B cells with allelic inclusion can normally expand in the periphery using double Ig knock-in mice, indicating the absence of negative selection against allelic inclusion B cells. In addition, we have shown that endogenous only B cells (IgMa–IgMb+) are also reduced in homozygotes (Fig. 2). Second, reduction of allelic inclusion B cells could be due to selective expansion of higher surface Ig-expressing cells by a self-antigen. However, the self-antigen (RBC) can kill self-reactive B cells 19. In fact, Id+ B cells of H+L mice decreased in homozygotes as compared with heterozygotes in spleen as well as in bone marrow (Fig. 3B and Fig. D). In addition, we have shown that non–self-reactive (H chain alone expressing) Tg (H3) B cells also show suppression of endogenous Ig expression (Fig. 2). These results cannot be explained by positive selection of self-reactive Ig expressing B cells by the self-antigen. Third, excess Tg Ig expression on surface may inhibit detection of endogenous Ig expression. It is unlikely that endogenous and Tg Ig molecules compete for surface expression in H+L5 and H+L6 spleen cells. This is because the surface Ig levels of homozygous H3, H+L6, and H+L5 cells are 909, 251, and 173 (MFI using the anti-IgMa Ab), respectively (Fig. 1 D), indicating that H+L5 and H+L6 B cells have not hit the ceiling of the surface Ig expression level. Sonoda and Rajewsky 50 have shown that there is no inhibitory mechanism for the H chain on the surface as long as it can associate with the L chain. It is inconceivable that the surface expression efficiency differs between H chains derived from the transgene and endogenous gene. The possibility that a lower detection efficiency by anti-IgMb Ab staining in the presence of large amounts of IgMa is also unlikely because the FACS® profiles of H3 spleen cells expressing large amounts of IgMa clearly show the presence of IgMa IgMb double-positive cells even in homozygotes (Fig. 2 B). Finally, the suppression efficiency of the endogenous locus may be increased in homozygotes simply because the frequency of silencing the transgene locus is reduced by doubling the number of the transgene locus in homozygotes. Assuming that this is the case, the efficiency of silencing of the transgene locus can be calculated from the endogenous H chain only cells shown in Fig. 2 A: H3, 0.06 / (0.06 + 0.11 + 6.50) = 0.009 in heterozygotes and 0.00144 = 0.01 / (0.01 + 0.03 + 6.9) in homozygotes. The value in homozygotes is 18 times of the expected value (0.009 x 0.009 = 0.000081) based on the simple statistics. Similar discrepancy was seen in the H+L5, H+L6, and H3 spleen cells (Fig. 2 B). In addition, homozygosity alters the number of Tg Id+ B cells in spleen and peritoneal cavity to the opposite direction. These considerations make the final possibility unlikely.
We have shown that H+L Tg mice have B cells expressing endogenous L chains together with the Tg H chain. These cells, expressing endogenous L chains in H+L mice, may be generated either by incomplete allelic exclusion or by receptor editing because the B cells which express the transgenes are self-reactive 5152. Nemazee and colleagues 535455 have suggested that interaction with autoantigens leads IgMlowIgD– bone marrow cells to undergo receptor editing but IgMhighIgD+ cells to undergo rapid apoptosis. On the other hand, Rusconi et al. 16 generated B cell hybridomas from anti-trinitrophenol antibody (anti-non-self) Tg mice that carried tandem joined H and L chain transgenes and demonstrated that the B cell hybridomas secreting the Tg antibody expressed the Tg L chain at about one-tenth of the level of coexpressed endogenous L chains. Endogenous L chain expression in their Tg mice is probably due to incomplete allelic exclusion because these B cells are unlikely to receive BCR stimulation by self-antigens to trigger receptor editing. Although we cannot exclude the possibility that receptor editing is involved in the appearance of B cells with endogenous L chains in our Tg mice, we think it less likely because of the following reason. If the expression of endogenous L chain is due to receptor editing induced by stimulation with the self-antigen, the mechanism to reduce the number of B cells with endogenous L chains by enhanced expression of self-reactive Ig should be clonal deletion. However, when B cells expressed more self-reactive Ig on surface, B cells with both Tg and endogenous L chains (IgMa+Idlow) are more efficiently reduced than Tg only B cells (IgMaId+), which are most likely eliminated by clonal deletion (Fig. 3). This observation is somewhat opposed to the expected efficiency of clonal deletion by the self-antigen because stronger BCR signaling will be induced in IgMaId+ cells than IgMaIdlow cells.
Although it is still controversial whether B-1 cells belong to an ontogenetically different B cell lineage from conventional B cells 34353637383940, B-1 and B-2 cells clearly constitute different subsets of B cells. In this study we have shown that the size of the Tg B-1 cell compartment is larger in homozygous than in heterozygous H+L mice (Fig. 4). Since Tg B-1 cells in heterozygous and homozygous mice show the same antigen specificity, our results suggest that the level of surface Ig expression directly influences the size of the Tg B-1 cell compartment. Our findings are consistent with the previous observations that defects of BCR signaling cause reduction of the B1 cell 5657, and loss of a BCR inhibitory molecule, SHP-1, increases the B1 cell number 5859606162. It is important to note that increased levels of autoreactive BCR induced augmented clonal deletion of B-2 cells in bone marrow and spleen but expansion of B-1 cells in the peritoneal cavity (Fig. 4). Increased expression of nonautoreactive Ig (H3) enhanced neither clonal deletion of B-2 cells nor expansion of B-1 cells. These results suggest that there are at least three levels of BCR signaling that regulate self-reactive B1 and B2 cell differentiation. At a lower level, self-reactive B-2 cells can be stimulated to induce receptor editing or to become anergic 53545563. At an intermediate signaling level, B-2 cells are clonally deleted and B-0 4041 and/or B-2 cells are induced to differentiate into B-1 cells, which migrate into the peritoneal cavity. At a strong signaling level, B-1 cells are also clonally deleted 19. It is tempting to speculate that at least a sizable fraction of peritoneal B-1 cells originate and expand from autoreactive B cells that are stimulated by self-antigens to a level strong enough to be activated but weak enough to avoid apoptosis.
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Acknowledgments |
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This work was supported by grants from the COE program from the Ministry of Education, Science, Sports and Culture of Japan.
Submitted: 10 February 1999
Revised: 16 June 1999
Accepted: 17 June 1999
S. Nisitani's present address is Howard Hughes Medical Institute, University of California, Los Angeles, 5-720 MRL, 675 Circle Dr. South, Box 951662, Los Angeles, CA 90095-1662.
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