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* Department of Biology, University of Pennsylvania, Philadelphia, PA 19104; and
Department of Cell Biology, Section Histology and Immunology, Faculty of Medical Sciences, University of Groningen, Groningen, The Netherlands
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Introduction |
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To address this issue, we generated Ig allotype chimeric mice under germfree conditions, using a protocol first described by Lalor et al. (20, 21) and applied in several studies by Baumgarth et al. (4, 5) under conventional conditions. In this model B1 and B2 cell-derived Abs can be distinguished based on different allotypes. Germfree mice were used to establish a balanced B1/B2 cell chimerism before microbial stimulation. Systemic and local intestinal immune responses were studied after colonization with Morganella morganii, Bacteroides distasonis, or segmented filamentous bacterium (SFB) and compared with conventionally reared chimeric mice. We show that B1 cells contribute a large amount of natural serum IgM under germfree conditions, which can be further induced by bacterial colonization. While B2 cells respond to intestinal colonization with the production of total and specific IgA, B1 cells contribute only a minimal amount of intestinal IgA in this model.
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Materials and Methods |
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Germfree BALB/c mice were bred and housed in the germfree facility at University of Pennsylvania (Philadelphia, PA) under sterile conditions in Trexler isolators (Standard Safety, McHenry, IL). Conventionally reared BALB/c mice were purchased from The Jackson Laboratory (Bar Harbor, ME), C.B-17 (C.B-Igh1b/IcrTac) mice were obtained from Taconic Farms (Germantown, NY) and housed in the animal facility of University of Pennsylvania.
To generate germfree Ig allotype chimeric mice, newborn germfree BALB/c mice (a allotype) were treated with 200 µg of anti-IgMa (clone DS-1) twice a week starting from day 1 after birth for a total of 10 injections in 32 days. On day 3 after birth, 2 x 106 PeC isolated by peritoneal lavage from conventionally reared, 8- to 12-wk-old C.B-17 donors (b allotype) were transferred by i.p. injection. Conventionally reared, Ig allotype chimeric animals were generated without anti-IgMa treatment by transferring 2 x 106 CB.17-derived PeC on days 1, 3, 5, and 28 after birth into BALB/c recipients.
Bacteria and monoassociation
M. morganii, a Gram-negative aerobic rod, related to the Proteus species, was originally isolated by Potter from mouse feces and was provided by A. Feeny (The Scripps Research Institute, La Jolla, CA). B. distasonis (TAC:ASF 519), a Gram-negative, anaerobic rod, was purchased from Taconic Farms. SFB, an obligate anaerobic, spore-forming, Gram-positive, segmented bacterium, related to Clostridia sp., was provided by H. Snel (University of Nijmegen, Nijmegen, The Netherlands). M. morganii was cultured in vitro in Brain Heart Infusion medium (Difco, Fisher Scientific, Pittsburgh, PA) under aerobic conditions. B. distasonis was grown in altered Schaedler broth (Difco), supplemented with 5% sterile FCS (Life Technologies, Grand Island, NY) under anaerobic conditions using the Aerogen system (OXOID, Basingstoke, U.K.). No in vitro culture method for SFB has been established to date. Therefore, spore-containing intestinal contents were isolated from SCID mice previously monoassociated with SFB, and fecal suspensions in PBS were used for further monoassociation. The purity of cultures or spore-containing fecal suspensions was verified microscopically in Gram-stained smears.
Eight-week-old germfree Ig allotype chimeric mice were transferred into sterile experimental Trexler isolators and monoassociated with M. morganii, B. distasonis, or SFB by oral inoculation with 200 µl (5 x 107 CFU) of in vitro cultured bacteria (M. morganii, B. distasonis) or spore-containing fecal suspensions (SFB). The expansion of bacteria in the gut and the persistence of intestinal colonization were monitored by in vitro culture of fecal contents (M. morganii, B. distasonis) or analysis of Gram-stained swabs from the luminal side of the intestinal tract (SFB).
Flow cytometry
Single-cell suspensions (2 x 105–106/sample) of PeC were stained for 20 min at 4°C with FITC-conjugated anti-IgDb (217-170; BD PharMingen, San Diego, CA), biotinylated anti-IgMb (AF6-78; BD PharMingen), FITC-conjugated anti-IgDa (AM89.1; BD PharMingen), and biotinylated anti-IgMa (DS-1; BD PharMingen). Cells were washed, and biotinylated Abs were revealed by PE-conjugated streptavidin (BD PharMingen). Single-cell suspensions of PP were stained for 20 min at 4°C with FITC-conjugated peanut agglutinin (PNA; Pierce, Rockford, IL; coupled to FITC in our laboratories as described previously (22)) and PE-conjugated anti-
L chain (Southern Biotechnology Associates, Birmingham, AL). Cells were washed and fixed in 1% paraformaldehyde in PBS and analyzed on a FACScan flow cytometer (BD Biosciences, Sunnyvale, CA). Germinal center (GC) B cells are defined as L chainlow/PNA+ cells, while memory B cells are excluded as L chainhigh/PNA-, as described previously (12). WinMDI2.8 software was used for evaluation (The Scripps Research Institute).
Analysis of Ab production in organ fragment cultures and serum
Conventionally reared, Ig allotype chimeric mice were sacrificed at 10 and 14 wk of age (n = 4/time point). Monoassociated mice were sacrificed on days 0, 7, 14, 28, 42, 56, and 70 after colonization (n = 2–3/time point), and blood was collected by heart puncture for serum analysis. The entire intestinal tract was surgically removed. For organ fragment culture (23), tissues were sterilized by sequential washes as described in detail previously (24). Pieces (3 x 3 mm) of duodenum, jejunum, ileum, cecum, and colon were incubated in 1 ml of Kennett’s HY medium, supplemented with 10% FBS, L-glutamine, penicillin, streptomycin, and gentamicin (all reagents from Life Technologies) for 7 days under a 90% O2/10% CO2 atmosphere at 37°C.
Total serum IgM was measured by RIA. Flexible polyvinyl plates (Serocluster; Costar, Cambridge, MA) were coated with 50 µl/well of 20 µg/ml goat anti-mouse F(ab')2 (Jackson ImmunoResearch Laboratories, West Grove, PA) and blocked with PBS containing 1% BSA (Sigma-Aldrich, St. Louis, MO), and serum was incubated overnight at 4°C. Bound IgM was detected using 125I-labeled anti-IgM (Southern Biotechnology Associates). Radioactivity of individual wells was measured using a 1272 Clini
gamma counter (LKB-Wallac, Gaithersburg, MD). A standard curve of monoclonal IgM was used to convert counts per minute to micrograms per milliliter.
To determine levels of IgMa or IgMb, 50 µl/well of 10 µg/ml anti-IgMa (DS-1; BD PharMingen) in PBS or 50 µl/well of 10 µg/ml anti-IgMb (AF6-78; BD PharMingen) in PBS was used for coating. Blocking and incubation were performed as described above, and bound Ab was detected with 125I-labeled anti-IgM. To convert counts per minute to nanograms per milliliter, standard curves were established for each allotype using purified monoclonal IgMa or IgMb, respectively.
Total IgA was measured by RIA as described previously (23), and a standard curve of purified, monoclonal IgA was used to convert counts per minute to nanograms per milliliter. To assess total IgAa and IgAb levels, plates were coated with 50 µl/well of 10 µg/ml anti-IgAa (HY15, a gift of Dr. M. Pawlita, originally generated and described by Potter and Lieberman (25), produced and purified in our laboratory) in PBS or 50 µl/well of 10 µg/ml anti-IgAb (HISM2, originally generated and produced in our laboratory, currently available at BD PharMingen) in PBS, blocking and incubation were performed as described, and bound Ab was detected with 125I-labeled anti-IgA (Southern Biotechnology Associates). Standard curves of purified IgAa or IgAb were used to convert counts per minute to nanograms per milliliter.
Bacteria-specific IgA was measured by RIA. Plates were coated with either 50 µl of 10 µg/ml bacterial sonicate (B. distasonis, SFB) overnight at 4°C or 100 µl/well freshly cultured bacteria in PBS (OD600 = 2) for 24 h at 37°C (M. morganii) and were blocked with 1% BSA in PBS. Incubation with organ fragment culture supernatant fluid was performed overnight at 4°C. Thereafter, plates were incubated for 4 h at room temperature with 125I-labeled anti-IgA. To assess levels of bacteria-specific IgAa or IgAb, plates were coated, blocked, and incubated with organ fragment culture supernatant fluid as described above. HY15 (anti-IgAa) and HISM2 (anti-IgAb) were used for allotype-specific IgA detection, and 125I-labeled anti-IgG1 and anti-IgG2a (Southern Biotechnology Associates) were used to detect bound HY15 and HISM2, respectively.
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Results |
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To study the contributions of B1 and B2 cells to the immune response against commensal bacteria, Ig allotype chimeric mice were generated under germfree and conventional conditions. Treatment of newborn germfree BALB/c mice (a allotype; recipient) with anti-IgMa for 32 days and transfer of PeC cells from C.B-17 mice (b allotype; donor) on day 3 after birth resulted in Ig allotype chimeric animals. As shown in Fig. 1, BALB/c- and C.B-17-derived PeC cells were specifically stained with Abs against surface IgMa and IgDa or IgMb and IgDb, respectively. In Ig allotype chimeric mice, most B1 cells in the PeC were of the donor allotype (IgMb high IgDb low), and importantly, no donor-derived B2 cells (IgMb low IgDb high) were detectable (Fig. 1). Most recipient-derived B cells were of the B2 phenotype (IgMa low IgDa high) even though some endogenous B1 cells (IgMa high IgDa low) were observed. Taken together these results show that most B1 cells in Ig allotype chimeric mice were donor derived, while all B2 cells were recipient derived. The chimerism (Table I) and cell numbers in the peritoneal cavity (data not shown) remained stable over the entire experimental period in both germfree and conventionally reared Ig allotype chimeric mice. The germfree chimeras were constructed identically to the method used by Lalor et al. (20) and can be compared directly to the original Lalor data as published. The reason why we went to the technically very difficult task of producing mice under germfree conditions is because of the comments on the original papers by Lalor et al. that in that instance B1 cells have an advantage over B2 cells because the latter have to develop from bone marrow precursors, while the antigenic stimulation by gut organisms is already present during that time for donor B1 cells. To avoid the same drawback, we tried a variation of the original Lalor method in conventional mice by continuously giving B2 cells the opportunity to react to the gut flora by making IgA. Using multiple injections and higher doses of B1 cells, we tried to overcome the described feedback inhibition (20). In fact, the transferred cells did establish donor B1 cells in the PeC in conventional mice at an 
2:1 ratio with respect to recipient B1 cells compared with the 6:1 ratio in germfree neonatal chimeras (Table I).
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Germfree Ig allotype chimeric animals showed levels of serum IgM comparable to those in conventional naive mice, and monoassociation stimulated additional IgM production (Fig. 2A). M. morganii induced a protracted IgM response with a peak on day 28 and continuously elevated levels until day 70. After monoassociation with B. distasonis serum IgM increased over the initial 14 days and thereafter waned. Colonization with SFB induced maximal production of serum IgM between days 14–28, followed by a return to baseline levels during the later phase of the experiment.
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Monoassociation with M. morganii, B. distasonis, or SFB induces GC reactions
Next we tested the stimulatory potentials of the different commensal bacteria on B1 and B2 cells in the gut. All three commensals led to activation of the intestinal mucosal immune system with marked GC reaction in PP, characterized by the appearance of PNA-binding B cells ( L chain low PNA binding, as defined by Lebman et al. (26); Fig. 3). While the GC reaction induced by B. distasonis peaked around day 28, monoassociation with M. morganii led to a prolonged activation of PNA-binding B cells in PP over 70 days. Colonization with SFB induced maximal GC reaction on day 14 after monoassociation. These results show that inoculation of germfree Ig allotype chimeric mice with each of the three commensals induced activation of a previously quiescent gut mucosal immune system.
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To assess mucosal Ab responses induced by intestinal colonization with M. morganii, B. distasonis, or SFB, IgA levels in organ fragment culture supernatant fluid were measured by RIA (Fig. 4). The mucosal immune system in germfree animals was quiescent, with barely detectable levels of intestinal IgA, but secretion of IgA was readily induced after monoassociation with any of the three commensals. Interestingly, the kinetics as well as the localization of maximal IgA production varied depending on the microorganism used for monoassociation. M. morganii stimulated IgA production mainly in the lower gastrointestinal tract (cecum, colon). Nevertheless, some stimulation of IgA secretion in the small intestine was observed. Colonization with B. distasonis induced an early IgA response, most pronounced in the small intestine and cecum, peaking on day 14 postinoculation. SFB stimulated an early IgA response in the upper gastrointestinal tract, with maximal levels around days 14–28. However, a slightly delayed response in cecum and colon followed around days 28–42. These data demonstrate that colonization with M. morganii, B. distasonis, or SFB stimulated intestinal IgA production at distinct sites and different times for each bacterium.
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Supernatant fluid of organ fragment cultures was analyzed for the presence of bacteria-specific IgA by RIA (Fig. 5). M. morganii-specific IgA was produced in all intestinal tissues, but in accordance with the findings for total IgA production, maximal levels of specific IgA were found in the colon (note the different scale). The production of specific IgA in the small intestine after colonization with B. distasonis reflected the data obtained for total IgA. Surprisingly, the highest level of B. distasonis-specific IgA was found on day 28 in the cecum. Monoassociation with SFB led to the rapid secretion of bacteria-specific IgA in the small intestine, followed by a specific response in the lower gastrointestinal tract. These data show that monoassociation with M. morganii, B. distasonis, or SFB not only stimulated the secretion of total IgA, but led to the production of Ag-specific IgA with distinct kinetics and localization of production for each bacterium.
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Next we analyzed the contributions of B1 and B2 cells to intestinal IgA production by determining levels of total and bacteria-specific IgAa and IgAb in organ fragment culture supernatant fluids. As shown in Fig. 6A, most of the total as well as bacteria-specific IgA induced by colonization was produced by B2 cells, with only a minor contribution of B1 cells, probably due to the paucity or even the absence of donor-derived B cells in the gut lamina propria. Similarly, analyses by immunofluorescence revealed only negligible numbers of IgAb-expressing cells in the gut lamina propria of chimeric mice (data not shown). Fig. 6B depicts the relative contribution of IgAa or IgAb, respectively, to total and bacteria-specific intestinal IgA. Germfree animals produced a low amount of IgA reactive with bacterial Ag compared with maximal levels of specific IgA after colonization, and B1 cells contributed significantly (45–73%) to this minute amount of naturally occurring bacteria-specific IgA (Fig. 6B). Monoassociation with M. morganii, B. distasonis, or SFB induced intestinal IgA production by B2 cells with very low contribution of B1 cells. Similar ratios of B1 and B2 cell-derived total IgA were found in conventionally reared animals. Thus, monoassociation with M. morganii, B. distasonis, or SFB as well as the presence of conventional microflora locally stimulated B2 cells to produce total and bacteria-specific intestinal IgA. The contribution of B1 cells to total intestinal IgA appeared to be limited (1–15%); however, some bacteria-specific B1 cell-derived IgA was detectable at late time points after monoassociation (15–20%).
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Discussion |
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-/- mice, it has been suggested that the production of most, if not all, of the natural IgA in the gut was specifically driven by particular microbial Ags and that it probably was the product of B1 cells developing in a T cell-independent fashion (19). While data obtained from adoptive transfer models clearly demonstrated that transferred B1 cells can establish a self-renewing population from which IgA-secreting plasma cells arise (14, 15, 16, 17, 18), these models might only partially reflect the normal physiological behavior of B1 cells and might not be applicable for quantitative analysis of B1 cell function in normal immunocompetent animals. Ig allotype chimeric animals, either conventionally reared or germfree and having a fully functional immune system, might more accurately reflect normal physiological conditions. Cotransfer of self-renewing B1 cells and a source of B2 cells, such as bone marrow, into conventionally reared recipients might favor the outgrowth and differentiation of B1 cells by exposing them to a stimulatory environment before the establishment of a mature B2 population. We therefore generated Ig allotype chimeric mice neonatally under germfree conditions, allowing a potentially more balanced establishment of functional populations of both B1 and B2 cells. The newborns were treated repeatedly with an anti-IgM allotype against the host allotype while being transferred with PeC cells at 3 days of age. After 8 wk we found a predominantly donor B1 cell population in the PeC, presumably normal populations of B2 cells derived from host bone marrow and a balanced donor/host contribution to circulating IgM.
Monoassociation of germfree Ig allotype chimeric animals with either M. morganii or SFB induced a rapid increase in B1-derived IgM with either simultaneous or subsequent stimulation of IgM production by B2 cells. Likewise, in our conventionally reared, neonatally developed, Ig allotype chimeric mice, 27% of total serum IgM was produced by B1 cells, a ratio similar to the proportions found at late time points after monoassociation of gnotobiotic animals. These data support the idea that B1 cells are a major source of natural IgM and might function as a link between innate and adaptive immune systems providing early humoral defense against microbial invasion (4, 5). This first line of defense can provide early systemic protection from potentially dangerous microorganisms, a vital precaution considering the importance of central organ systems for immediate survival. Interestingly, B. distasonis stimulated mainly B2 cells, while B1 cell-derived IgM remained at levels comparable to those in germfree animals. These results suggest that B1 cells need specific stimulation to mount additional IgM and that this stimulation depends on the colonizing microorganism.
We used unfractionated PeC cells from conventionally reared donors as a source of B1 cells. Such unfractionated populations also contain donor B2 cells as well as some activated T cells. Also, since these cells derived from conventionally reared donors, they could have been previously selected for reactivity with a vast array of environmental Ags different from the microbe used to monoassociate, thereby precluding an effective response against the microbes selected for our study. Our arguments to minimize these potentially confusing aspects of our model are that 1) the donor-derived cells were of the B1 phenotype, as shown by FACS analysis of PeC isolated from Ig allotype chimeric mice, and did establish in PeC, but contributed little to gut IgA production; and 2) donor-derived B1 cells were functional, i.e., they contributed to the natural serum IgM in germfree animals as well as to the IgM response after monoassociation. Thus, a rapid decay of transferred B1 cells with the specificities to respond to any particular microbe seems improbable, particularly since their product is often rather close to a germline specificity.
However, monoassociation of formerly germfree, adult mice with commensal bacteria is different from the naturally occurring codevelopment of the immune system and flora in conventionally reared animals. The induction of GC reactions upon monoassociation of adult germfree mice might favor stimulation and differentiation of B2 cells and therefore lead to the predominance of B2-derived IgA in our system. Conventionally reared Ig allotype chimeric mice were generated by repeated injection of donor-derived PeC into newborn mice without additional anti-IgMa treatment. This modification allowed undisturbed development of both donor-derived and endogenous B cells during natural colonization. The resulting chimerism was comparable to that of anti-IgMa-treated germfree Ig allotype chimeric mice with a majority of donor-derived B1 cells in the PeC. However, in conventionally reared Ig allotype chimeric mice the contribution of B1 cells to the intestinal IgA production was only marginal, and most gut IgA was produced by B2 cells.
Monoassociation with each of the three commensals also induced GC reactions in PP of the small intestine and led to the production of intestinal IgA with distinct kinetics and particular main sites of IgA secretion for each bacterium. These data are in accordance with a recent report by Jiang et al. (27) demonstrating a clear correlation between the localization of SFB in the intestine and the IgA response by the host. Taken together, our results show that all three microorganisms interact with their host in a way that leads to activation of the formerly quiescent gut mucosal immune system.
Until recently the mechanisms involved in recruiting IgA-committed B cells to the intestinal lamina propria have been only poorly understood. It has been established that 
47 integrin mediates binding of lymphocytes to mucosal addressin cell adhesion molecule-1 and is therefore crucial for lymphocyte homing to the gut (28). Work by Bowman et al. (29) has shown that TECK/CCL25, expressed by intestinal epithelial cells, is a potent and selective chemoattractant for IgA-secreting B cells. Their work focused on B cell populations obtained from mesenteric lymph nodes, PP, and spleen. As B2 cells represent the major B cell population in these organs, it might well be that the mechanisms described by these authors, while true for the recruitment of B2 cells, only marginally apply for B1 cells. Several mechanisms involved in the accumulation of B1 cells in the peritoneal cavity, Ig class switching, and migration to the lamina propria have been described (30, 31, 32), and Fagarasan et al. (33) have demonstrated the potential of B220+IgM+ lamina propria cells, presumably B1 cells, for in situ class switching and differentiation to IgA-producing cells. However, they also showed that the mechanism describedapplies for a very small fraction of lamina propria B cells compared with PP B cells. Taken together, these studies suggest that different mechanisms are involved in the attraction of B1 and B2 cells to the lamina propria, and that the quantitative importance of these mechanisms might vary. We cannot completely exclude that some of the intestinal IgAa is B1 derived in our model, as the Ig allotype chimeric mice showed the presence of some endogenous B1 cells. However, if B1 cells contribute a major proportion of the intestinal IgA production in our model, we would expect the donor-derived B1 cells to participate in a quantitatively significant way.
How can we reconcile our observations with respect to the findings in other systems? The potential of B1 cells to produce intestinal IgA has been shown in transfer models (14, 15, 16, 17, 18). However, the immunologic environment in these settings is greatly altered. The function of B2 cells is impaired either by delayed development of a functional B2 population (transfer models) or by attenuated GC reaction in PP and disturbed cognate B-T cell interaction (TCR-/-/- mice). The SCID mouse lacks PP GC reactions, and the TCR-/-/- mouse has only minimal gut PP GC reactions, probably due to B2 cells, and they do not lead to appreciable affinity maturation (point mutations) (34). Such B2 responses may account for the observed microbial Ag dependence of natural IgA production in TCR-/-/- mice (19). Possibly the cytokines present in these vestigial GC reactions are sufficient to allow minimal clonal expansion and switching to IgA expression. Our model system includes normal GC reactions in PP, favoring specific B2 cell development. Thus, we believe our proffered model is likely to be more physiologically normal and relevant to the immunocompetent mouse than other models.
In summation, our data demonstrate that B1 cells are a major source of natural IgM and can mount an early serum IgM response given the right antigenic stimuli, but that Ig class switching and migration to the gut after colonization with commensal bacteria are dominated by B2 cells and not B1 cells. Our model suggests that the physiologic contribution of B1 cells to IgA production in response to colonization with commensal organisms is limited, and most of the total as well as specific intestinal IgA is produced by B2 cells.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Nicolaas A. Bos, Department of Cell Biology, Section of Histology and Immunology, Faculty of Medical Sciences, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. E-mail address: n.a.bos{at}med.rug.nl
3 Abbreviations used in this paper: PP, Peyer’s patch(es); GC, germinal center; PeC, peritoneal cavity cells; PNA, peanut agglutinin; SFB, segmented filamentous bacterium.
Received for publication July 10, 2002. Accepted for publication March 5, 2003.
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transgenic mice are derived from B-1 (Ly-1B) cells. Int. Immunol. 5:1317.47 integrin mediates lymphocyte binding to mucosal vascular addressin MAdCAM-1. Cell 74:185.[Medline]
-chain selectively influences the development of the common mucosal immune system independent IgA-producing B-1 cells in mucosa-associated tissues. J. Immunol. 162:821.This article has been cited by other articles:
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