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* Trudeau Institute, Saranac Lake, NY 12983; Departments of
Internal Medicine and
Microbiology, Immunology, and Molecular Genetics, University of Kentucky and
Veterans Administration Medical Center, Lexington, KY 40536
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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RI and III (FcRKO), indicating that P. carinii-specific IgG partially mediates opsonization and clearance of P. carinii. Opsonization of organisms by complement did not compensate for the lack of specific IgG or FcR, since C3-deficient and C3-depleted FcRKO mice were still able to clear P. carinii. Finally, µMT and CD40KO chimeric mice had reduced numbers of activated CD4+ T cells in the lungs and lymph nodes compared with wild-type mice, suggesting that B cells are important for activation of T cells in response to P. carinii. Together these data indicate that P. carinii-specific IgG plays an important, but not critical, role in defense against P. carinii. Moreover, these data suggest that B cells also mediate host defense against P. carinii by facilitating CD4+ T cell activation or expansion. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although it is widely accepted that both CD4+ T cells and macrophages are involved in host defense against P. carinii, it has been underappreciated that B cells are also required for resolution of P. carinii infections. Indeed, several groups have now shown that B cell-deficient (µMT) mice are highly susceptible to P. carinii infection (11, 12, 13). Although it is not known how B cells contribute to the resolution of P. carinii infection, there have been a number of studies indicating that IgG Abs produced by B cells can mediate clearance of P. carinii (14, 15, 16, 17, 18, 19). First, T cell-depleted mice with large amounts of circulating P. carinii-specific IgG either due to previous immunization or vaccination by P. carinii Ag-loaded dendritic cells resulted in clearance of organisms after a secondary challenge (14, 15, 16). Furthermore, passive immunoprophylaxis using a mAb specific for P. carinii was shown to protect immunodeficient animals from PCP (17, 18, 19). P. carinii-specific IgG is presumed to mediate the clearance of P. carinii by opsonizing the organisms which then targets them for phagocytosis via the Fc receptors expressed on the alveolar macrophages.
Although these previous studies showed that P. carinii-specific Ab can have a positive impact on host defense against PCP, adoptive transfer models have shown that in the total absence of B cells or Ab, P. carinii-specific CD4+ effector cells are sufficient to induce the clearance of P. carinii from the lungs (8, 20). Thus, since it is still unclear whether Ab is necessary for clearance of primary P. carinii infection, it is still not known whether the protection provided by B cells is due to Ab production or to other B cell-dependent immune mechanisms. To directly test whether P. carinii-specific IgG is necessary for clearance of P. carinii, we have used a mixed bone marrow transplantation approach to generate mice whose B cells are unable to produce class-switched P. carinii-specific Ig. We report that chimeric mice that lack CD40 expression on B cells, but retain CD40 on other APC, do not produce P. carinii-specific IgG, but are able to clear P. carinii from the lungs, albeit with delayed kinetics. Likewise, we show that FcRKO and C3-depleted FcRKO mice have delayed resolution to P. carinii challenge compared to wild-type (WT) mice, yet eventually resolve the infection. These data suggest that Ab production by B cells promotes, but is not necessary for, the clearance of P. carinii from the lungs of infected mice. Furthermore, since B cells are obligate for resolution of P. carinii infection, these data strongly suggest that B cells contribute in Ab-independent ways to the resolution of P. carinii, perhaps through Ag presentation, cytokine production, and/or interactions with T cells. In agreement with this hypothesis, we found that CD4+ T cell activation and/or expansion in P. carinii-infected B cell-deficient mice was significantly reduced compared with normal animals. Thus, B cells appear to play multiple roles in the resolution of P. carinii infection.
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Materials and Methods |
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Adult C57BL/6J, B6.129S2-Tnfsf5tm1Imx (CD40KO), B6.129S4-C3tm1Crr (C3KO), and B6.129S2-Igh-6tm1Cgn (µMT) mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Cby.129(B6)-FcerIgtm1 (FcRKO) mice were obtained from Taconic Farms (Germantown, NY) and BALB/cBy mice were obtained from the National Cancer Institute. C3-deficient BALB/c mice were generated by i.p. injection of 25 µg of cobra venom factor from Naja naja (Sigma-Aldrich, St. Louis, MO) every 3 days as has been previously described (21). For some experiments, chimeric mice were generated as described below at the Trudeau Institute and shipped to the University of Kentucky before infection with P. carinii. All experimental mice were housed in the Lexington, KY Veterans Administration Medical Center veterinary medical unit in sterile, filter-topped cages and were given sterile food and water ad libitum. A colony of C.B17 SCID mice originally obtained from Taconic Farms were used to maintain a source of P. carinii (a gift from A. Harmsen, Montana State University, Bozeman, MT) for infection of experimental mice. Mice used for the generation of chimeras were maintained on sulfamethoxazole/trimethoprim in the drinking water on a 3-day on, 4-day off schedule. The drug was withdrawn a full 2 wk before infection with P. carinii.
Generation of mixed chimeras
To generate mice whose B cells were deficient in CD40, mixed chimeras were made. Recipient µMT mice were lethally irradiated with 9.5 Gy from a 156Cs source and 107 bone marrow cells injected i.v. on the same day. Recipient mice received injections of either 75% µMT plus 25% C57BL/6 bone marrow cells, 100% µMT cells, or 75% µMT plus 25% CD40KO bone marrow cells. This regimen resulted in mixed chimeric mice whose B cells lacked CD40 but whose macrophages and dendritic cells were largely CD40 positive. Mice were checked for reconstitution of the B and T cell compartments 10 wk posttransplant by staining PBL for FACS analysis as described below. Mice that did not have reconstituted B lymphocytes were eliminated from further experimentation.
Enumeration and inoculation of P. carinii organisms
For isolation of organisms for inoculation, lungs were excised from P. carinii-infected SCID mice and pushed through stainless steel mesh in HBSS. Cell debris was removed by centrifugation at 100 x g for 2 min. Aliquots of lung homogenates were spun onto glass slides, fixed in methanol, and stained with Diff-Quik (Dade International, Miami, FL). P. carinii nuclei were enumerated by microscopy. Mice to be infected were anesthetized lightly with halothane gas and 5 x 106–107 P. carinii organisms injected intratracheally in 100 µl of PBS. For determination of lung P. carinii burden, right lung lobes were excised, minced, and digested in RPMI 1640 medium supplemented with 2% FCS, 1 mg/ml collagenase A, and 50 U/ml DNase for 1 h at 37°C. Digested lung fragments were pushed through mesh screens and aliquots were spun onto glass slides and stained with Diff-Quik for microscopic enumeration as previously described (7). Lung burden is expressed as log10 P. carinii nuclei per right lung lobes and the limit of detection was 3.23.
Isolation of cells from alveolar spaces, lungs, and lymph nodes
Mice were killed by exsanguination under deep halothane anesthesia. The lungs were lavaged with HBSS containing 3 mM EDTA. After removing an aliquot for enumeration of P. carinii organisms as described above, erythrocytes were removed from lung digests using a hypotonic lysing buffer, cells were washed, and single-cell suspensions were enumerated. Tracheobronchial lymph nodes (TBLN) were pushed through mesh screens in HBSS and enumerated.
Flow cytometric analysis of lung and lymph node lymphocytes
Lung lavage, lung digest, and TBLN cells were washed in PBS with 0.1% BSA and 0.02% NaN3 and stained with appropriate concentrations of fluorochrome-conjugated Abs specific for murine CD4, CD44, CD62 ligand (L), IgM, and CD40. Abs were purchased from BD PharMingen (San Diego, CA). Expression of these molecules on the surface of lymphocytes was determined by multiparameter flow cytometry using a FACSCalibur cytofluorometer (BD Biosciences, Mountain View, CA).
P. carinii-specific ELISA
Blood was collected from the abdominal aorta under halothane anesthesia and sera were frozen at -80°C. A crude sonicate of P. carinii (10 µg/ml) was coated onto microtiter plates for 2 h and coated wells were blocked with 5% dry milk in HBSS supplemented with 0.05% Tween 20 for 1 h. Test sera were serially diluted and incubated in plates overnight (4°C). Plates were washed extensively and bound Ab was detected using appropriate dilutions of alkaline phosphatase-conjugated specific Abs (anti-IgM, IgG, IgA). After 4 h at 37°C, plates were washed and developed using p-nitrophenyl phosphate at 1 mg/ml in diethanolamine buffer. A405 or end point titer expressed as the log10 inverse dilution at which the A405 was <0.1 is reported.
Statistical analysis
Differences between experimental groups were determined using Student’s t test or ANOVA, followed by Student-Neuman-Keuls post hoc test where appropriate. Differences were considered statistically significant when p < 0.05. SigmaStat statistical software (SPSS, Chicago, IL) was used for all analyses.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been previously reported that mice deficient in B cells (µMT mice) are susceptible to PCP (11, 12). Furthermore, it is known that CD40L expression on T cells is necessary for resolution of P. carinii infection since individuals with mutations in the CD40L gene (X-linked hyper-IgM syndrome) are susceptible to opportunistic infections including P. carinii, Cryptosporidium, and Candida (22, 23). In addition, blocking the CD40-CD40L interaction in P. carinii-infected mice with CD40L-specific Ab resulted in the inability to resolve PCP (20). Since CD40L expression on T cells is required for P. carinii clearance and B cell activation, germinal center formation, and class switching to IgG, we first examined whether CD40-deficient mice were as susceptible as µMT mice to intranasal inoculations of P. carinii. As shown in Fig. 1, WT C57BL/6 mice control the infection by day 20 and have either cleared or have very low lung burdens of P. carinii by day 35 postinfection. In some experiments, WT mice cleared the infection even faster than 5 wk postchallenge (data not shown). In contrast, µMT and CD40KO mice had steadily increasing lung P. carinii burdens over the 5 wk of the experiment (Fig. 1). These mice succumb to infection when the lung P. carinii burden approaches log10 8.0. To test whether the class-switched Ab response was normal in the CD40KO mice, serum was collected from the mice at various times postinfection and the levels of P. carinii-specific IgM and IgG were determined. As expected, the B cell-deficient mice did not produce detectable quantities of P. carinii-specific Ab of any isotype (Fig. 2). In contrast, the CD40KO and WT mice produced comparable levels of serum P. carinii-specific IgM (Fig. 2). However, as predicted, the CD40KO mice were unable to produce any P. carinii-specific IgG (Fig. 2).
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The previous results indicate that both B cells and CD40 are required for resolution of P. carinii infection. The results also indicated that P. carinii-specific IgM produced by CD40KO mice was not sufficient to provide protection nor was it able to reduce the severity of infection. In addition, since neither CD40KO nor µMT mice are able to produce class-switched P. carinii-specific Ab, the results could suggest that class-switched IgG Ab is obligate for clearance of primary P. carinii infection. However, CD40 is expressed on a number of cell types, including B cells, macrophages, and dendritic cells, and is important for the activation of all of these cells types (24, 25). Furthermore, CD40-CD40L interactions between APC and T cells are critical for optimal CD4+ T cell priming (24, 25, 26, 27, 28).
To separate the requirement for CD40 expression on B cells to induce activation and class switching from its functional role(s) on other cell types, three different types of mixed bone marrow chimeric mice were generated according to the protocol described in Materials and Methods. The first group consisted of µMT hosts that were reconstituted with µMT bone marrow. These µMT chimeric mice were completely B cell deficient but produced all other cell types (data not shown). The second group consisted of µMT hosts that were reconstituted with a 3:1 ratio of µMT and CD40KO bone marrow. B cells were present in these CD40KO chimeric mice, but the B cells in these mice were derived from CD40KO bone marrow and were unable to express CD40 (Fig. 3). In contrast, the majority (75%) of all other cell types in the CD40KO chimeric mice, including macrophages and dendritic cells, were derived from CD40-sufficient bone marrow and were competent to express CD40 (Fig. 3). In the final group, µMT hosts were reconstituted with a 3:1 ratio of µMT and WT bone marrow. The B cells as well as all other cell types in these WT chimeric mice were derived from CD40-sufficient bone marrow (Fig. 3). Ten weeks postreconstitution, the chimeric mice were infected with P. carinii and P. carinii-specific Ab titers were determined at various times postinfection. As expected, the µMT chimeras did not make any detectable Ab of any isotype while the WT chimeras produced P. carinii-specific IgM, IgG, and IgA Abs (Figs. 4 and 5). In contrast, the CD40KO B cell chimeras were unable to generate P. carinii-specific IgG or IgA, despite making P. carinii-specific IgM (Figs. 4 and 5). Indeed, P. carinii-specific IgG levels in the CD40KO B cell chimeras never rose above the background level seen with the µMT chimeric mice at any time point postinfection (Fig. 4).
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R1 and III knockout (KO) mice
The delayed clearance of P. carinii infection observed in the CD40KO chimeras could have been due to the absence of P. carinii-specific IgG. Alternatively, the delay may have been due to some other B cell function that is dependent on CD40 expression, such as costimulation of T cells via CD80 or CD86 or Ag presentation after up-regulation of MHC class II expression (24, 26). To test whether P. carinii-specific IgG facilitates rapid clearance of infection, mice deficient in Fc receptors I and III and Fc
receptors (FcRKO) were infected with P. carinii. It is known that Fc receptor expression on phagocytes allows the phagocyte to bind, phagocytose, and kill organisms that have been opsonized by specific IgG, thus FcRKO mice provide a good model to test the efficacy of IgG in eliminating P. carinii. As shown in Fig. 7, there was a delay in the clearance of P. carinii in FcRKO mice compared with WT controls. WT BALB/c mice had reduced P. carinii burden 100-fold compared with FcRKO mice by day 20 postinfection (Fig. 7). However, by day 31, all mice had undetectable lung P. carinii burdens. The delayed clearance of P. carinii in FcRKO mice was not due to differences in Ab production as the relative amounts of P. carinii-specific IgM and IgG found in the sera were not significantly different in the FcRKO mice compared with the WT mice (Fig. 7). Together these data suggest that the delay in clearance of the organisms in the FcRKO mice was due to the inability to phagocytose opsonized P. carinii. However, it is clear that in the absence of FcR-dependent opsonization of P. carinii, other compensatory mechanisms must stimulate phagocytosis and clearance of P. carinii.
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B cells are obligate for protection from PCP, yet a deficiency in P. carinii-specific IgG or in the FcR necessary for binding IgG-opsonized organisms delays clearance of P. carinii but does not prevent resolution of the infection. These data indicate that B cells must participate either directly or indirectly in the killing of P. carinii via additional immune mechanisms. One additional Ab-dependent mechanism in which B cells could contribute to P. carinii resolution is to produce P. carinii-specific IgM that could be used to activate complement, resulting in opsonization of the P. carinii. This possibility seemed unlikely since CD40KO mice produce P. carinii-specific IgM, yet die with equivalent kinetics as mice that completely lack B cells (Fig. 1). However, C3 activation can also take place via Ab-independent mechanisms. Therefore, to further rule out the possibility that the complement component C3 or its downstream effectors can compensate for the absence of IgG or FcR, we tested whether C3 is required for host defense against P. carinii. C3KO mice were infected intratracheally with 107 organisms and P. carinii lung burden was determined. As shown in Fig. 8, there was no difference in the P. carinii lung burdens of WT and C3KO mice at days 15 and 29 postinfection. These data indicate that C3 is not necessary for clearance of P. carinii. Finally, to test whether opsonization of organisms by C3 cleavage products in combination with P. carinii-specific IgM or IgG is necessary for P. carinii clearance from the lung, C3 was depleted from FcRKO mice using cobra venom factor. As shown in Table I, all mice were able to clear P. carinii infections from the lungs by day 28 postinfection. Together, these data demonstrate that C3 and FcRs as well as P. carinii-specific IgG are not obligate for the clearance of P. carinii from the lungs of infected mice.
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The results described above indicate that P. carinii-specific Ab, particularly class-switched Ab, contributes to, but is not obligate for, the clearance of P. carinii from the lungs. However, B cells are clearly required, suggesting that B cells must also mediate clearance of P. carinii by mechanisms independent of Ab production. To test whether B cells might also regulate the CD4+ T cell response, we determined the number of activated T cells in the draining TBLN and lungs of P. carinii-infected WT, µMT, and CD40KO B cell chimeras. As shown in Fig. 9, the number of activated CD4+CD62Llow T cells increased in the draining TBLN of WT chimeric animals over the course of infection, peaking at day 20. In contrast, the µMT and CD40KO chimeric mice had reduced numbers of activated CD4+ T cells in the TBLN from day 10 through day 40 (Fig. 9). The percentage of CD4+ T cells with an activated phenotype was considerably lower in the TBLN of µMT and CD40KO chimeric mice than in the WT chimeras at day 20 (Fig. 9). Indeed, by day 30 postinfection, the number of activated CD4+ T cells in the draining TBLN had actually begun to decline in the B cell-deficient µMT chimeric mice (Fig. 9), despite the fact that the P. carinii burden was quite high in these animals (see Fig. 6). In the CD40KO B cell chimeric animals, the number of activated T cells remained low, but relatively constant, from day 10 through day 40 (Fig. 9).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R-deficient mice resolved the infection by day 30. Together, these results suggest that opsonization of P. carinii by IgG is not sufficient to mediate the clearance of P. carinii from the lungs. Although it has recently been reported that IgA is produced at mucosal surfaces in µMT mice (34), P. carinii-specific IgA was not detected in either the lungs or sera of CD40KO chimeras, indicating that specific IgA did not compensate for the lack of IgG in this model.
Since the CD40KO chimeric mice did clear P. carinii infection and were capable of producing P. carinii-specific IgM, it was possible that IgM production by B cells is necessary for resolution of infection with P. carinii. Indeed, recent experiments have demonstrated that mAbs of the IgM isotype directed against the KEX1 protein of P. carinii were able to control growth of P. carinii when injected intranasally into SCID mice (19). Additionally, it has been shown that IgM Abs can mediate clearance of another fungal pathogen, Cryptococcus neoformans (35). However, our data using CD40KO mice (Figs. 1 and 2) indicated that P. carinii-specific IgM is not sufficient to control P. carinii infection since these mice produced specific IgM but were unable to clear the pathogen. In addition, although IgM is a powerful activator of the complement system, C3-deficient mice were also able to resolve the P. carinii infections, suggesting that P. carinii-specific IgM is unlikely to play a significant complement-dependent role in controlling P. carinii lung burden. Finally, C3 and FcR double-deficient mice were able to resolve P. carinii infection, although with somewhat delayed kinetics. Taken together, our data strongly suggest that Ab and complement-mediated opsonization of P. carinii can facilitate but are not sufficient to mediate immune protection to primary P. carinii infection.
Since it is generally accepted that alveolar macrophages are ultimately responsible for clearance of P. carinii organisms from the lungs (9), targeting of the organisms to these macrophages must be mediated by additional mechanisms that are independent of FcRs and complement. As described above, we think that it is unlikely that these alternate clearance mechanisms rely on T cell-dependent Ab production. Alternatively, Ezekowitz et al. (36) reported that in the absence of serum, mannose receptors on macrophages facilitated phagocytosis of P. carinii organisms. It was later determined that macrophage mannose receptors bound to 
-mannan residues of gpA (36, 37), the major surface glycoprotein expressed on P. carinii. It has also been reported that 
-glucan receptors on macrophages interact with P. carinii organisms as do host proteins, including fibronectin, vitronectin, and surfactant proteins A and D (38, 39, 40). These proteins all have in common the ability to bind to carbohydrate moieties found on the surfaces of many microorganisms and may be responsible for phagocytosis of the organisms in the absence of specific IgG, FcRs, or complement. However, none of these mechanisms compensate for the lack of B cells since µMT mice were unable to clear P. carinii infection.
Given that B cells are obligate for the clearance of a primary infection of P. carinii (11, 12) and that P. carinii-specific, high-affinity, class-switched Ab does not appear to be necessary for the resolution of infection, it is likely that B cells contribute to the immune response via non-Ab-mediated mechanisms. To explore this possibility, we determined whether the absence of B cells altered the CD4+ T cell response. In the experiments presented here, we show that T cell activation and/or expansion in the draining TBLN and lungs of P. carinii-infected mice was largely reduced in B cell-deficient and CD40KO chimeric mice.
There are at least two different hypotheses that could be used to explain why T cell expansion is reduced in the infected µMT and CD40KO chimeric mice. First, it has been recently shown by Cyster and colleagues (41) that splenic T cell zone development is controlled by B cells. They show that lymphotoxin--producing B cells promote T cell and dendritic cell accumulation in the spleen during early postnatal development of the spleen. Although it is theoretically possible that this developmental defect in B cell-deficient mice is responsible for the reduced T cell activation in the P. carinii-infected chimeric animals, we think that this is highly unlikely. First, B cell-deficient mice have reduced numbers of T cells and dendritic cells in the spleen but not in the lymph nodes (41). We observed a clear difference in the number of activated T cells in the draining lymph nodes of infected µMT and CD40KO chimeric mice (Fig. 8). Second, the number of total CD3+ cells in the lymph nodes of uninfected µMT chimeric mice was equivalent to the WT chimeric mice (data not shown), indicating that the "defect" in the expansion/activation of CD4+ T cells in the µMT chimeric animals occurs after infection and is not due to a pre-existing developmental deficiency in the animals. Third, all of the mice in this experiment were bone marrow reconstituted µMT animals and thus all of the chimeric mice have equivalently defective spleens since bone marrow reconstitution does not fix the developmental defect in these mice (41). Finally, and most importantly, we observed the same deficiency in T cell activation/expansion in B cell-sufficient CD40 chimeric animals. Thus, the reduction in activated T cells in the lymph node and lung after P. carinii infection cannot simply be explained by the loss of B cell-derived lymphotoxin- in the spleen. Instead, we propose that CD40-expressing B cells are needed for optimal T cell activation/expansion after P. carinii infection. Given that activated B cells can efficiently present Ag to T cells, we hypothesize that B cells might help to regulate the activation or expansion of the primed Ag-specific CD4+ T cells. It has been shown that ligation of CD40 on naive B cells by CD40L on T cells is required for up-regulation of B7 molecules that are necessary for costimulation of T cells during Ag presentation (24, 42). Furthermore, B cells are known to be essential for expansion of T cells in lymph nodes (29, 30, 31). Thus, Ag-presenting CD40-expressing B cells might mediate the costimulation of T cells during P. carinii infection. Additional experiments will be necessary to determine the molecular mechanism(s) by which B cells assist in the activation and expansion of Ag-specific CD4+ T cells after primary infection.
Despite the unanswered question of how B cells modulate CD4+ T cell responses to P. carinii infection, our data strongly suggest that B cells contribute in multiple ways to the ultimate resolution of primary P. carinii infection. Surprisingly, we observed that despite the absolute requirement for B cells in the host defense against P. carinii, specific IgG, FcRs, and complement are not necessary for clearance, although these immune mechanisms do facilitate more rapid clearance of the pathogen. Thus, B cells must play additional Ab-independent roles during primary infection, perhaps by regulating the strength or quality of the CD4+ T cell response.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Beth A. Garvy, Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, University of Kentucky Chandler Medical Center, Room MN668, 800 Rose Street, Lexington, KY 40536. E-mail address: bgarv0{at}uky.edu
3 Abbreviations used in this paper: PCP, P. carinii pneumonia; KO, knockout; TBLN, tracheobronchial lymph node; WT, wild type; L, ligand.
Received for publication November 25, 2002. Accepted for publication May 21, 2003.
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References |
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chain expression in developing B cells. Nat. Immunol. 2:625.[Medline]
release from alveolar macrophages through a -glucan-mediated mechanism. J. Immunol. 150:3932.[Abstract]
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