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Infection and Immunity, July 2005, p. 4427-4431, Vol. 73, No. 7
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.7.4427-4431.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Endogenous CD4+ CD25+ Regulatory T Cells Play No Apparent Role in the Acute Humoral Response to Intact Streptococcus pneumoniae

Katherine S. Lee, Goutam Sen, and Clifford M. Snapper*

Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814

Received 16 November 2004/ Returned for modification 7 January 2005/ Accepted 4 March 2005


   ABSTRACT
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Immunoglobulin G (IgG) antiprotein and antipolysaccharide responses to intact Streptococcus pneumoniae are CD4+-T-cell dependent and therefore might be under the negative control of CD4+ CD25+ regulatory T cells. Injection of anti-interleukin 2 receptor {alpha} (anti-IL-2R{alpha}) MAb to deplete regulatory T cells, injection of agonistic MAb against glucocorticoid-induced tumor necrosis factor receptor family-related protein to inhibit regulatory-T-cell function, and adoptive transfer of regulatory-T-cell-depleted CD4+ T cells into athymic nude mice each had no effect on either the primary or secondary protein- or polysaccharide-specific IgG response to intact S. pneumoniae. Surprisingly, anti-IL-2R{alpha} MAb also had no effect on the IgG response to intact S. pneumoniae in MyD88–/– mice or to a soluble protein-polysaccharide conjugate injected into wild-type mice in the absence of adjuvant. Collectively, these data are the first to suggest that, in contrast to their role in limiting chronic cell-mediated immunity, regulatory T cells may play no significant role in an acute humoral immune response to an intact extracellular bacterial pathogen.


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Endogenous CD4+ CD25+ regulatory T cells account for 5 to 10% of peripheral CD4+ T cells and, due to their broad range of antigen specificities, can limit immune responses to many different self as well as foreign antigens (17, 22). Although many publications have described a role for regulatory T cells in down-regulating chronic cell-mediated immune responses such as those seen in autoimmunity (26, 27), tumor immunity (14, 18, 23), transplantation tolerance (5, 28), and infections caused by Plasmodium yoelii (7), Leishmania major (2), Onchocerca volvulus (19), human immunodeficiency virus, and cytomegalovirus (1), very little is known regarding a potential role for regulatory T cells in the acute humoral response to extracellular bacteria.

The potential for regulatory T cells to influence humoral immune responses is suggested by the emergence of autoantibodies in the absence of a functional regulatory-T-cell population (17, 22) and the observation that regulatory T cells could inhibit the elicitation of anti-double-stranded DNA antibodies when coadministered with CD4+ T helper cells to nonautoimmune mice (21). In addition, immunization of mice expressing transgenes for both specific B- and T-cell antigen receptors with the relevant, linked foreign antigens elicited a hyper immunoglobulin E (IgE) response that was inhibited by transfer of regulatory T cells (4). Finally, FoxP3 transgenic mice overexpressing scurfin, a protein implicated in inducing the regulatory-T-cell phenotype (6, 11), showed a markedly reduced trinitrophenol-specific Ig response to trinitrophenol-keyhole limpet hemocyanin in complete and incomplete Freund adjuvant (8).

CD25 (interleukin 2 receptor {alpha} [IL-2R{alpha}]) is constitutively expressed on regulatory T cells. Injection of anti-IL-2R{alpha} MAb (PC61) (12) has been shown to selectively deplete regulatory T cells in vivo and abrogate suppression (23). Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is also constitutively expressed on regulatory T cells (13, 24). An agonistic GITR-specific MAb, DTA-1, can abrogate the suppressor activity of regulatory T cells both in vitro and in vivo (13, 24). GITR expression can be induced on activated effector CD4+ T cells, where it can act as a costimulatory molecule (25).

We previously reported that both in vivo protein- and polysaccharide (PS)-specific IgG responses to intact Streptococcus pneumoniae were dependent on T-cell receptor {alpha}/ß+ CD4+ T-cell help (9, 29). These data led us to examine a potential role for regulatory T cells in limiting the T-cell-dependent IgG antiprotein and anti-PS responses to intact S. pneumoniae in vivo. To our knowledge, this is the first study to explore the potential role of regulatory T cells in an acute humoral response to an intact extracellular bacterium in vivo.

The preparation of S. pneumoniae capsular type 14, soluble conjugates of PPS14-PspA and C-PS-PspA, and other reagents used in this study has been described by us previously (9). Rat IgG2a anti-mouse GITR MAb (clone DTA-1) (24), a kind gift from Shimon Sakaguchi (Kyoto University, Kyoto, Japan), rat IgG1 anti-mouse CD25 (IL-2R{alpha}) MAb (clone PC61) (12), purchased from the American Type Culture Collection, and isotype MAb controls (rat IgG2a anti-Escherichia coli ß-galactosidase [clone GL117] and rat IgG1 anti-E. coli ß-galactosidase [GL113]), kind gifts of Fred D. Finkelman (University of Cincinnati Medical Center, Cincinnati, OH), were purified from ascites by ammonium sulfate precipitation and passaged over a protein G column. DTA-1-biotin was kindly provided by Ethan Shevach (National Institutes of Health, Bethesda, MD).

Determination of antigen-specific serum titers of various Ig isotypes by enzyme-linked immunosorbent assay (ELISA), magnetic bead cell sorting, flow cytometry, adoptive transfer studies, and statistical analysis were also performed as described previously (9, 30). Female BALB/c and athymic nude mice were purchased from the National Cancer Institute (Frederick, MD). Mice were used between 6 and 8 weeks of age and were maintained in a pathogen-free environment at the Uniformed Services University of the Health Sciences (Bethesda, MD). MyD88–/– mice were obtained from S. Akira (Osaka University, Osaka, Japan) and bred and genotyped in our facility (10). For spleen cell proliferation in vitro, spleen cells (1 x 106/ml) were treated with various concentrations of either GL117 (control MAb) or DTA-1 for various times, and incorporation of [3H] thymidine (1 µCi/well) was measured during the last 6 h of culture.

Treatment with anti-IL-2R{alpha} MAb (PC61) to selectively deplete CD4+ CD25+ T cells (regulatory T cells) has no effect on the humoral response to various doses of live intact S. pneumoniae capsular type 14. Administration of PC61, an anti-IL-2R{alpha} MAb, results in the selective depletion of regulatory T cells (3). Flow cytometric analysis was performed using spleen cells from mice treated with either PC61 or control MAb GL113 and stained with anti-CD4 and either PC61 or another anti-CD25 MAb, 7D4, which recognizes a different epitope of CD25. In accordance with other studies (23), we found that regulatory T cells were markedly reduced when PC61 was given 1 day prior to immunization with live S. pneumoniae capsular type 14 (Fig. 1A). We injected three doses of live S. pneumoniae capsular type 14 (5 x 106, 1 x 107, or 5 x 107 CFU per mouse) intraperitoneally (i.p.), which led to induction of various serum titers of anti-PPS14 (capsular pneumococcal polysaccharide type 14), anti-PC (phosphorylcholine determinant of C-polysaccharide [C-PS]), and anti-PspA (pneumococcal surface protein A). PC61 or isotype-matched control MAb, GL113, was injected 16 h prior to immunization, and sera were collected on day 0 (prebleed), day 7 (anti-PPS14 and anti-PC) and day 14 (anti-PspA). As illustrated in Fig. 1B, PC61 had no significant effect on the primary serum titers of IgG anti-PPS14, anti-PC, or anti-PspA relative to treatment with GL113, at any of the three immunization doses used.



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  		FIG. 1. PC61 treatment does not alter the humoral response to various doses of live S. pneumoniae capsular type 14. (A) Flow-cytometric analysis of spleen cells from mice treated with 1 mg PC61 i.p. 1 day prior to sacrifice. Left two panels, spleen cells from control (GL113) and PC61-treated mice stained with anti-CD4-fluorescein isothiocyanate (FITC) and anti-CD25-PE (PC61); right two panels, spleen cells from control and PC61-treated mice stained with anti-CD25-FITC (7D4) and anti-CD4-PE. (B) Seven mice per group were injected i.p. with either 1 mg PC61 or 1 mg GL113 and 16 h later with the respective dose of live S. pneumoniae capsular type 14. Sera were obtained on days 0, 7, and 14 for determination of antigen-specific IgG titers by ELISA. Data are presented as serum titers of anti-PPS14 and anti-PC (day 7) and titers of anti-PspA (day 14). Values are arithmetic means ± standard errors of the means. Data from one of three representative experiments are shown.

 
Treatment with an agonistic anti-GITR MAb (DTA-1) does not alter the in vivo antiprotein or antipolysaccharide IgG isotype response to heat-killed intact S. pneumoniae capsular type 14. Agonistic anti-GITR MAb (DTA-1) inhibits regulatory-T-cell function both in vitro and in vivo (13, 24). We confirmed that our purified unlabeled DTA-1 preparation was capable of binding to GITR by demonstrating that it specifically blocked staining of activated T cells with biotin-labeled DTA-1 (conjugated with avidin-phycoerythrin [PE]), the latter kindly provided by Ethan Shevach (NIH, Bethesda, MD) (data not shown). Purified DTA-1 was also confirmed by ELISA to be a rat IgG2a antibody as previously reported (24) (data not shown). Finally, we confirmed in vitro that DTA-1 had functional antisuppressor activity by demonstrating spontaneous proliferation of spleen cells in vitro upon addition of DTA-1 but not with the isotype control, GL117 (Fig. 2A), as previously reported (24). We next immunized mice i.p. with 2 x 108 CFU heat-killed S. pneumoniae capsular type 14, 16 h after i.p. injection of 1 mg each of either control MAb, GL117, or DTA-1, and gave them boosters of an equal amount of S. pneumoniae capsular type 14 alone on day 14. Sera were obtained prior to immunization and 7, 14, and 21 days later. Administration of DTA-1 had no significant effect on the primary or secondary PspA-, PC-, or PPS14-specific IgM (data not shown) or IgG isotype responses to S. pneumoniae capsular type 14 compared to control GL117 (Fig. 2B) or saline (data not shown). Injecting a combination of PC61 and DTA-1 at the time of primary immunization with heat-killed S. pneumoniae capsular type 14 also had no significant effect on the primary or secondary humoral response (data not shown). Further, DTA-1 given only at the time of secondary immunization with heat-killed S. pneumoniae capsular type 14 had no effect on the elicitation of the memory IgG response in mice previously primed with S. pneumoniae capsular type 14 alone (data not shown).



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  		FIG. 2. DTA-1 treatment does not alter the primary or secondary humoral immune response to heat-killed S. pneumoniae capsular type 14. (A) Spontaneous proliferation of spleen cells (1 x 106/ml) in the presence of various concentrations of control MAb (GL117) or DTA-1. (B) Seven mice per group were injected i.p. with either 1 mg DTA-1 or 1 mg of control MAb (GL117), and 16 h later with 2 x 108 CFU of heat-killed S. pneumoniae capsular type 14 i.p. Mice were boosted on day 14 with a similar dose of S. pneumoniae capsular type 14. Sera were obtained on days 0, 7, 14, and 21 for determination of antigen-specific Ig isotype titers by ELISA. Values are arithmetic means ± standard errors of the means. Data are from one of three representative experiments.

 
Adoptive transfer of splenic CD4+ CD25– T cells into athymic nude mice restores IgG anti-PspA, anti-PC, and anti-PPS14 responses to heat-killed, intact S. pneumoniae capsular type 14 to levels no greater than that observed using total CD4+ T cells. We previously reported that adoptive transfer of CD4+ T cells into S. pneumoniae capsular type 14-immunized, T-cell-deficient, athymic nude mice could restore the IgG responses specific for PspA, PC, and PPS14 (9). To directly test a potential role for CD4+ CD25+ T cells in suppressing a S. pneumoniae capsular type 14-induced humoral response, spleen cells from wild-type mice were magnetically sorted into two populations, CD4+ (both CD25+ and CD25–) and CD4+ CD25– (Fig. 3A), and then adoptively transferred into athymic recipients 16 h prior to immunization with S. pneumoniae capsular type 14. Seven and fourteen days after immunization, sera were collected to measure PC-, PspA-, and PPS14-specific IgG titers. Figure 3B shows that the removal of regulatory T cells had no effect on the CD4+ T-cell-mediated enhancement of titers of IgG specific for PPS14, PC, or PspA.



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  		FIG. 3. Adoptive transfer of CD4+ CD25– T cells into athymic nude recipients restored S. pneumoniae capsular type 14-induced PspA-, PC-, and PPS14-specific IgG titers to levels no greater than that observed for total CD4+ T cells. (A) Flow-cytometric analysis of spleen cells that underwent magnetic bead selection for CD4+ (both CD25+ and CD25–) (left) and CD4+ CD25– (right) T cells. (B) Seven athymic nude mice each were injected intravenously with either phosphate-buffered saline, 3 x 106 CD4+ T cells, or 3 x 106 CD4+ CD25– T cells in the tail vein and challenged 16 h later with 2 x 108 CFU of heat-killed S. pneumoniae capsular type 14. Values are arithmetic means of the peak titers for PspA (day 14)-, PC (day 7)-, and PPS14 (day 7)-specific-IgG titers plus standard errors of the means. Data are from one of two representative experiments.

 
Treatment with anti-IL-2R{alpha} MAb (PC61) to deplete regulatory T cells has no effect on the humoral response to heat-killed, intact S. pneumoniae capsular type 14 in MyD88–/– mice or to soluble protein-polysaccharide conjugates injected in the absence of adjuvant. Intact S. pneumoniae expresses a number of ligands for Toll-like receptors (TLRs) (20). TLR-mediated immune activation has been shown to abrogate regulatory-T-cell activity, thus allowing initial induction of immunity (15, 16). We previously demonstrated that MyD88–/– mice are markedly defective in their innate immune response to S. pneumoniae and exhibit a striking reduction in type 1 IgG isotypes (IgG3, IgG2b, and IgG2a) specific for PPS14, PC, and PspA (10). We thus reasoned that regulatory-T-cell activity would still be operative in S. pneumoniae-immunized MyD88–/–, but not wild-type mice, and that regulatory-T-cell depletion would enhance humoral immunity in the former, but not the latter. As shown in Fig. 4A, although specific IgM and IgG responses to heat-killed S. pneumoniae capsular type 14 were lower in MyD88–/– than wild-type mice, PC-61 had no significant effect on the humoral response in either group of mice. Further, regulatory-T-cell depletion using PC-61 had no effect on induction of IgM or IgG anti-PPS14, anti-PC, or anti-PspA in wild-type mice immunized with a mixture of soluble PPS14-PspA and C-PS-PspA conjugates in saline (Fig. 4B). The ability of PC-61 to deplete regulatory-T-cell in vivo was independently confirmed prior to the latter experiments (Fig. 1A).



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  		FIG. 4. PC-61 treatment does not alter the humoral immune response to intact S. pneumoniae capsular type 14 in MyD88–/– mice or to soluble protein-polysaccharide conjugates injected in saline into wild-type mice. (A) MyD88–/– and wild-type mice (seven per group) were injected i.p. with 1 mg of PC-61 or 1 mg of GL113 followed 16 h later by 2 x 108 CFU heat-killed S. pneumoniae capsular type 14 i.p. Sera were obtained on days 0, 7, and 14 for determination of antigen-specific Ig isotype titers by ELISA. (B) Wild-type mice (seven per group) were injected i.p. with 1 mg of PC-61 or 1 mg of GL113 followed 16 h later by 1 µg each of PPS14-PspA and C-PS-PspA in saline i.p. Sera were obtained on days 0, 7, and 14 for determination of antigen-specific Ig isotype titers by ELISA. One experiment each was performed.

 
In summary, we used a number of complementary, conventional approaches to assess the potential role of regulatory T cells in vivo in order to mitigate against the potential pitfalls inherent in any one approach. Our data suggest that, in contrast to what is observed during many distinct types of chronic cell-mediated immune responses, including infections with intracellular pathogens, regulatory T cells may not play a significant role in acute humoral responses to extracellular bacteria. Extracellular bacteria elicit early TLR-dependent innate immunity followed by a T-cell-dependent adaptive humoral response but are typically eliminated rapidly with no subsequent chronic phase. However, under conditions of chronic immune stimulation often observed with intracellular pathogens and typically associated with a more limiting level of microbial stimulation, effector T cells may re-establish a more homeostatic balance with regulatory T cells to limit excessive T-cell-driven immunity and tissue damage while allowing continued T cell immunity (2).


   ACKNOWLEDGMENTS
 
Opinions and assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense or the Uniformed Services University of the Health Sciences.

We thank Andy Lees (Biosynexus, Inc., Gaithersburg, MD) for provision of PC-keyhole limpet hemocyanin, PPS14-PspA, and C-PS-PspA, Shizuo Akira (Osaka University, Osaka, Japan) for providing MyD88–/– breeding pairs, Ethan Shevach (National Institutes of Health, Bethesda, MD) for biotin-DTA-1, Fred D. Finkelman (University of Cincinnati Medical Center, Cincinnati, OH) for provision of GL113 and GL117 cell lines, and Shimon Sakaguchi (Kyoto University, Kyoto, Japan) for the DTA-1 cell line.

This work was supported by NIH grants 1R01 AI49192 and 1R01 AI46551 and the USUHS Dean's Research and Education Endowment Fund.


   FOOTNOTES
 
* Corresponding author. Mailing address: Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814. Phone: 301-295-4590. Fax: 301-295-1640. E-mail: csnapper{at}usuhs.mil. Back

Editor: J. N. Weiser


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Infection and Immunity, July 2005, p. 4427-4431, Vol. 73, No. 7
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.7.4427-4431.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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