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Infection and Immunity, May 2009, p. 1976-1980, Vol. 77, No. 5
0019-9567/09/$08.00+0     doi:10.1128/IAI.01091-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Generation of Antibody Responses to Pneumococcal Capsular Polysaccharides Is Independent of CD1 Expression in Mice

Leen Moens,^1, Axel Jeurissen,^1, Stefan Nierkens,² Louis Boon,³ Luc Van Kaer,⁴ Ahmad Kasran,⁵ Greet Wuyts,¹ Jan L. Ceuppens,⁵ and Xavier Bossuyt^1*

Experimental Laboratory Medicine, Department of Medical Diagnostic Sciences, Faculty of Medicine, Catholic University Leuven, Leuven, Belgium,¹ Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, University Medical Centre Nijmegen, The Netherlands,² Bioceros B.V., Utrecht, The Netherlands,³ Laboratory of Experimental Immunology, Department of Pathophysiology, Faculty of Medicine, Catholic University Leuven, Leuven, Belgium,⁵ Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee⁴

Received 2 September 2008/ Returned for modification 23 October 2008/ Accepted 27 January 2009

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Streptococcus pneumoniae is a bacterial microorganism that frequently causes serious infection, particularly in children and the elderly. Protection against infection with S. pneumoniae is based mainly on the generation of antibodies to the pneumococcal capsular polysaccharides (caps-PS), but the mechanisms responsible for the generation of anticapsular antibodies remain incompletely understood. The aim of the present study was to evaluate the role of CD1-restricted T cells in the antibody response to caps-PS. When immunized with Pneumo23, wild-type mice and CD1 knockout mice on BALB/c and C57BL/6 backgrounds generated immunoglobulin M (IgM) and IgG antibody responses to soluble caps-PS that were comparable. Similar results were obtained after immunization with heat-inactivated S. pneumoniae. The IgM and IgG antibody response of wild-type mice to Pneumo23 was not affected by an antagonizing monoclonal anti-CD1 antibody treatment. In summary, our data provide evidence that the antibody response to caps-PS is generated independently of CD1 expression.

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Streptococcus pneumoniae is a major human pathogen. Infections with S. pneumoniae result in substantial morbidity and mortality, particularly in young children, the elderly, and immunocompromised patients (26). In various animal species and in humans, protection against S. pneumoniae infection is mediated by antibodies against pneumococcal capsular polysaccharides (caps-PS) and surface proteins (2, 4, 21).

caps-PS are classified as T lymphocyte-independent type 2 (TI-2) antigens (24). While T lymphocytes are not required for the generation of antibody responses against TI-2 antigens, they can influence the antibody response to these antigens (24). In the case of caps-PS, the role of T lymphocytes in the generation of antibody responses might be more important than was initially thought. There is now evidence that T lymphocytes may support the antibody response to TI-2 antigens via several pathways (14). The magnitude of the antibody response to caps-PS is regulated both positively and negatively by distinct subsets of thymus-derived T lymphocytes. It has been reported that CD4⁺ T cells have positive effects on the antibody response to caps-PS, whereas CD8⁺ T cells have a suppressive effect. The presence of these two distinct types of T cells with opposing regulatory functions with respect to the immune response to soluble caps-PS has been demonstrated in vivo in mice and in vitro with human lymphocytes (1, 8, 10). SCID/SCID mice reconstituted with B lymphocytes and CD4⁺ T lymphocytes mounted a higher specific immunoglobulin M (IgM) antibody response to soluble pneumococcal caps-PS than SCID/SCID mice reconstituted with only B lymphocytes (12, 15). Murine spleen cells depleted of CD8⁺ T lymphocytes mounted a higher immune response to soluble caps-PS than total murine spleen cells, whereas spleen cells depleted of CD4⁺ T cells elicited only a weak antibody response (15). Similarly, the human IgM and IgG antibody response to soluble pneumococcal caps-PS was strongly dependent on CD4⁺ T cells (13). Several reports have provided evidence that CD4⁺ T cells enhance the IgG antibody response to pneumococcal polysaccharides after immunization of mice with intact S. pneumoniae (19, 37). The antipolysaccharide antibody response after immunization with conjugated polysaccharide serotype 3 was higher in CD8-deficient mice than in control mice, a finding attributed to CD8 T lymphocyte-mediated suppression of the antipolysaccharide immune response (34).

In a provocative study, Kobrynski et al. (20) reported that CD1-restricted T cells and major histocompatibility complex (MHC) class I-dependent CD8⁺ cells are essential for the anti-caps-PS immune response. These findings set forth a new paradigm for humoral responses to caps-PS in which CD1 expression as well as a subset of CD8⁺ cells is required to provide helper function for antibody production against TI-2 caps-PS, akin to the role of MHC class II-restricted CD4⁺ cells for the generation of antibody responses to protein antigens (20). The MHC class I-like protein CD1 is expressed on antigen-presenting cells and is required for the presentation of lipids and glycolipids to T lymphocytes (25, 28, 29).

The findings of Kobrynski et al. (20), suggesting that CD8⁺ T cells are essential for the IgG antibody response to caps-PS, are at odds with many other experimental data (1, 8, 10, 12, 13, 15, 19, 34, 37) that support the concept that CD4⁺ T cells have a positive effect on the antipolysaccharide immune response. Because of this controversy and because Kobrynski et al. (20) did not investigate the role of CD1 expression in the generation of IgM anti-caps-PS antibody responses, we reevaluated the role of CD1 expression in the IgM and IgG antibody response to pneumococcal polysaccharides. Our results revealed that CD1 expression was not required for the generation of IgM and IgG antibody responses to caps-PS.

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Materials. Pneumo23 was obtained from Sanofi Pasteur MSD Belgium. Pneumococcal caps-PS were obtained from ATCC, Manassas, VA. C-polysaccharide was obtained from Statens Serum Institute, Denmark. The hybridoma producing monoclonal blocking antibodies to murine CD1 (20H2) was obtained from ATCC. Polyclonal rat IgG was from 10 P's, Zandhoven, Belgium. Peroxidase-conjugated goat anti-mouse IgM and IgG were from Nordic Immunological Laboratories, Tilburg, The Netherlands. Goat serum and phosphate-buffered saline (PBS) were from Gibco BRL, Life Technologies Ltd., Paisley, Scotland. 3,3',5,5'-Tetramethylbenzidine (TMB) was purchased from Dako Diagnostics N.V./S.A., Heverlee, Belgium. H₂SO₄ was from Merck KgaA, Darmstadt, Germany. Covalink and Maxisorb enzyme-linked immunosorbent assay (ELISA) plates were obtained from Nunc Brand Products, Nalge Nunc International, Denmark. -Galactosylceramide was purchased from Alexis Pharmaceuticals. Gamma interferon (IFN-) capture and biotin-conjugated antibodies were obtained from BD Pharmingen.

Mice. BALB/c mice and C57BL/6 mice were bred at the Proefdierencentrum of the Catholic University Leuven in Heverlee, Belgium. CD1d knockout mice backcrossed to BALB/c mice (C;129S-Cd1tm1Gru) were purchased from The Jackson Laboratories, Bar Harbor, ME. CD1 knockout mice on a C57BL/6 background were a gift from L. Van Kaer (Vanderbilt University, Nashville, TN). These mice lack functional Cd1d1 and Cd1d2 expression, as well as the natural killer cell-like T-cell subset (35). Animals were used at the age of 6 to 8 weeks and were kept under a standard protocol with free access to pelleted food and water. All mouse strains were held in a room with 12-h/12-h light/dark cycle. Approval of the study was granted by the local ethics committee of the Catholic University Leuven.

Immunization of mice. Mice were immunized intraperitoneally (i.p.) with Pneumo23 or with 2 x 10⁸ CFU of intact heat-killed S. pneumoniae (strain 071697 [serotype 3] and strain 071710 [serotype 14], obtained from J. Verhaegen, Laboratory Medicine, University Hospital Leuven, Belgium). The vaccine was diluted 1/25 in 0.9% NaCl. Five hundred microliters of this diluted vaccine was given i.p. After 14 days, blood was drawn by cardiac puncture, and anti-caps-PS antibodies were detected by ELISA. In experiments in which the effects of the anti-CD1 antibody 20H2 were studied, 500 µg of 20H2 was injected i.p. 1 day before immunization with Pneumo23. Five hundred micrograms of hamster IgG control antibody was injected i.p. in the control group.

ELISA for detection of anti-caps-PS antibodies. Anti-caps-PS antibodies were detected as previously described (23). Briefly, a Covalink ELISA 96-well plate (caps-PS3) or a Maxisorp ELISA 96-well plate (caps-PS1, caps-PS4, caps-PS9N, and caps-PS14) was coated overnight at 37°C with pneumococcal polysaccharides (final concentration, 3 µg/ml in 0.09% NaCl). The next day, the plate was washed four times with 0.05% Tween 20 in PBS. Thereafter, the plate was blocked for 1 h at 37°C with 10% goat serum in PBS. Serum was treated at room temperature for a minimum of 30 min with pneumococcal C-polysaccharide (5 µg/ml PBS containing 2% goat serum) and PS-22F (5 µg/ml PBS containing 2% goat serum) to remove anti-C-polysaccharide antibodies and non-Streptococcus pneumoniae-specific antibodies, respectively. Serum was added to the wells and incubated for 2 h at 37°C. After washing four times with 0.05% Tween 20 in PBS, peroxidase-conjugated goat anti-mouse IgM or goat anti-mouse IgG at a dilution of 1/5,000 was added to the wells. The plate was incubated for 1.5 h at 37°C. Thereafter, TMB was added for color development. After 30 min, the reaction was stopped with 0.5 M H₂SO₄. Plates were read at 450 nm.

ELISA for quantification of IFN-. The levels of IFN- in culture supernatants were determined by sandwich ELISA. Nunc Maxisorb 96-well plates were coated overnight at 4°C with anti-IFN- capture antibodies and blocked for 4 h with PBS-Tween-3% milk powder at room temperature. Samples and cytokine standards were added in several dilutions and incubated overnight at 4°C. Plates were incubated with rat anti-mouse IFN- conjugate for 1 h at room temperature, followed by streptavidin-horseradish peroxidase incubation for 45 min. Finally, TMB substrate (0.1 mg/ml) was added, and the color reaction was stopped with 2 M H₂SO₄. Absorbance was measured at 450 nm.

Culture of D1 dendritic cells. The D1 cell line, a long-term growth factor-dependent immature splenic dendritic cell line derived from B6 mice, was cultured as described previously (36).

Statistical analysis. Differences in antibody levels were evaluated with the Mann-Whitney U test.

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To study the role of CD1 expression in presenting caps-PS to T lymphocytes, the anti-caps-PS antibody response was studied in CD1 knockout mice. Control mice and CD1 knockout mice on a BALB/c background and on a C57BL/6 background were immunized with Pneumo23, and the antibody response to caps-PS was measured 2 weeks later. As shown in Fig. 1B and C, the IgM as well as the IgG anti-caps-PS antibody responses to serotype 3 and serotype 4 were not significantly different in CD1 knockout and wild-type mice. Similar results were found for other serotypes (serotype 1, 9N, and 14) (data not shown).

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FIG. 1. Role of CD1 in the pneumococcal antipolysaccharide immune response. Mice were immunized with Pneumo23 or heat-inactivated S. pneumoniae serotype 3. The IgG and IgM response to caps-PS serotype 3 or serotype 4 was measured 14 days after immunization. The results show the absorbance values (mean ± 1 standard deviation) at multiple serum dilutions for IgG and IgM. The data shown are from a representative experiment out of two (B), three (D), and four (A) experiments. (A) BALB/c wild-type mice were treated with rat IgG (n = 4; ) or with anti-CD1 (20H2) (n = 4; ) and immunized with Pneumo23. (B) BALB/c wild-type mice (n = 4; ) and CD1 knockout mice on a BALB/c background (n = 4; ) were immunized with Pneumo23. (C) C57BL/6 wild-type mice (n = 5; ) and CD1 knockout mice on a C57BL/6 background (n = 4; ) were immunized with Pneumo23. (D) C57BL/6 wild-type mice (n = 5; ) and CD1 knockout mice on a C57BL/6 background (n = 5; ) were immunized with heat-inactivated S. pneumoniae serotype 3.

Next, we also evaluated the effect of anti-CD1 antibody (20H2) treatment on the antibody response to Pneumo23. Anti-CD1 monoclonal antibody has previously been shown to affect listeriosis in mice (22). In order to confirm that the 20H2 antibody was effective in blocking CD1 function, we investigated whether 20H2 was able to inhibit cytokine production by CD1-restricted natural killer T cells in response to stimulation with the potent agonist -galactosylceramide (23). For this purpose, we measured the effect of 20H2 on IFN- production after stimulation of spleen cells cultured with D1 dendritic cells in the presence of -galactosylceramide. The results are shown in Fig. 2 and illustrate that 20H2 strongly inhibited -galactosylceramide-mediated IFN- production.

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FIG. 2. Anti-CD1 antibody inhibits -galactosylceramide-induced IFN- production by splenocytes. D1 cells were cultured in medium, medium supplemented with -galactosylceramide (100 ng/ml), or vehicle. After 24 h, the cells were incubated for 1 h with anti-CD1 (20H2, 20 ng/ml) or isotype control antibody. Splenocytes were added to the cultures, and IFN- in the supernatant was determined after 24 h of incubation. Error bars indicate standard deviations.

The results of the in vivo experiments in which we evaluated the effect of anti-CD1 treatment on the anti-caps-PS immune (serotype 3) response are shown in Fig. 1A and illustrate that neither the IgM nor the IgG immune response to caps-PS was blocked by 20H2. The amount of antibody administered to the animals was similar to the amount of antibody administered by Szalay et al., who found an effect of anti-CD1 on listeriosis infection (33). Similar results were found for serotype 4. Taken together, these data suggested that CD1 expression is not required for the overall antibody response to caps-PS.

Finally, we studied the immune response to inactivated intact S. pneumoniae serotype 3 in C57BL/6 CD1 knockout mice and in control mice. In intact S. pneumoniae serotype 3, the polysaccharides are presented as part of a whole organism, whereas in Pneumo23, the polysaccharides are presented as soluble antigens. The IgM and IgG antibody responses to serotype 3 in intact S. pneumoniae were comparable in CD1 knockout mice and control mice (Fig. 1D). Similar results were found for serotype 14 (results not shown).

Taken together, our results indicate that CD1 expression does not play an important role in the immune reaction to caps-PS, independent of the way that the antigen is presented.

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CD1 molecules are expressed on antigen-presenting cells and are known to present lipids and glycolipids to CD4⁺ and CD4^– CD8^– T lymphocytes (18, 30). CD1 molecules are associated with β₂-microglobulin, a characteristic shared with classical MHC class I proteins, with which they share sequence homology (7). The naturally occurring CD1-presented antigens appear to be lipids or glycolipids (31). The crystal structure of CD1 indicates that the lipid tail of the antigen anchors into the hydrophobic cavity of CD1, leaving the hydrophilic saccharide groups protruding from the CD1 molecule and accessible for interactions with T lymphocytes (3, 31).

Kobrynski et al. found that CD1 knockout mice were severely deficient in IgG production to caps-PS, suggesting a role of CD1 in the presentation of caps-PS by antigen-presenting cells to T lymphocytes (20). We found (i) that the anti-caps-PS immune response in CD1 knockout animals was comparable to the response in wild-type animals and (ii) that administration of a blocking anti-CD1 antibody did not affect the anti-caps-PS immune response. Taken together, our data indicate that CD1 expression does not influence the antibody immune response to caps-PS. This is in line with the ultrastructure of the CD1 molecule, which has a large hydrophobic groove that binds the hydrophobic part of the presented antigen (38). Taking the findings together, the role of CD1 in the production of antibody to pneumococcal caps-PS is controversial. It is unclear how these different observations with respect to the role of CD1 and the role of CD8⁺ T cells might be explained. Few data on this issue are available in the literature. It has been reported that the macrophage-mediated clearance of Pseudomonas aeruginosa from the lung is CD1d dependent (27). Moreover, Kawakami et al. reported a critical role of V14⁺ CD1⁺ natural killer T cells in the innate phase of host protection against S. pneumoniae (17).

The mechanism by which T lymphocytes are activated by caps-PS and antigen-presenting cells remains largely undefined. It is generally believed that caps-PS do not bind to MHC class II molecules (11). This was confirmed in studies using MHC class II-deficient mice, which had normal antibody responses to TI-2 antigens (6). Furthermore, it was shown that allogeneic T lymphocytes were able to stimulate the anti-caps-PS antibody response (9). Cobb et al. (5), however, found that zwitterionic polysaccharides (e.g., caps-PS serotype 1) are processed to low-molecular-weight carbohydrates by a nitric oxide-dependent mechanism in endosomes and bind to MHC class II inside antigen-presenting cells. These antigens elicited a potent CD4⁺ T-cell response in vitro and in vivo (16), which required direct interaction of T cells with HLA-DR-bearing antigen-presenting cells. The immune response to zwitterionic polysaccharides depends on the translocation of HLA-DR to the cell surface and requires costimulation via B7-2 and CD40 on activated antigen-presenting cells (32). In the present paper, we provide evidence that the antibody response to caps-PS is generated independently of CD1 expression.

 
This work was supported by grants from the Research Council of the Catholic University Leuven, the Research Foundation-Flanders, and GlaxoSmithKline. Xavier Bossuyt is a senior clinical investigator and Leen Moens is a postdoctoral fellow of the Research Foundation-Flanders (FWO).

 
* Corresponding author. Mailing address: University Hospital Leuven, Laboratory Medicine/Immunology, Campus Gasthuisberg, CDG 7th Floor, Herestraat 49, B-3000 Leuven, Belgium. Phone: 32 16 34 70 09. Fax: 32 16 34 79 31. E-mail: Xavier.bossuyt{at}uz.kuleuven.ac.be

Published ahead of print on 2 February 2009.

Editor: V. J. DiRita

These authors equally contributed to the study.

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Infection and Immunity, May 2009, p. 1976-1980, Vol. 77, No. 5
0019-9567/09/$08.00+0     doi:10.1128/IAI.01091-08
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