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Inducible Costimulator Protein Controls the Protective T Cell Response Against Listeria monocytogenes¹

Hans-Willi Mittrücker^2,*, Mischo Kursar^*, Anne Köhler^*, Donna Yanagihara, Steven K. Yoshinaga and Stefan H. E. Kaufmann^*

^* Max Planck Institute for Infection Biology, Berlin, Germany; and Amgen, Inc., Thousand Oaks, CA 91320

	Abstract

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The inducible costimulator protein (ICOS) was recently identified as a costimulatory molecule for T cells. Here we analyze the role of ICOS for the acquired immune response of mice against the intracellular bacterium Listeria monocytogenes. During oral L. monocytogenes infection, low levels of ICOS expression were detected by extracellular and intracellular Ab staining of Listeria-specific CD4⁺ and CD8⁺ T cells. Blocking of ICOS signaling with a soluble ICOS-Ig fusion protein markedly impaired the Listeria-specific T cell responses. Compared with control mice, the ICOS-Ig treated mice generated significantly reduced numbers of Listeria-specific CD8⁺ T cells in spleen and liver, as determined by tetramer and intracellular cytokine staining. In contrast, the specific CD8⁺ T cell response in the intestinal mucosa did not appear to be impaired by the ICOS-Ig treatment. Analysis of the CD4⁺ T cell response revealed that ICOS-Ig treatment also affected the specific CD4⁺ T cell response. When restimulated with listerial Ag in vitro, reduced numbers of CD4⁺ T cells from infected and ICOS-Ig-treated mice responded with IFN- production. The impaired acquired immune response in ICOS-Ig treated mice was accompanied by their increased susceptibility to L. monocytogenes infection. ICOS-Ig treatment drastically enhanced bacterial titers, and a large fraction of mice succumbed to the otherwise sublethal dose of infection. Thus, ICOS costimulation is crucial for protective immunity against the intracellular bacterium L. monocytogenes.

	Introduction

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Antigen recognition by the TCR induces the activation of T cells. However, TCR-mediated signals alone are insufficient, and additional costimulatory signals are required for efficient activation. CD28 can provide such cosignals for T cells, but there are numerous situations where T cell activation occurs independently of CD28 (1). Recently, inducible costimulator (ICOS), a homolog of CD28, was cloned and shown to provide costimulatory signals to T cells (2, 3, 4). Yet, several features of ICOS distinguish it from CD28. Expression of ICOS is restricted to activated T cells, and ICOS does not bind to B7.1 or B7.2, but recognizes a third member of the B7 protein family, the B7RP-1 molecule (2, 3, 4, 5). B7RP-1 is expressed on B cells, macrophages, and a subpopulation of dendritic cells and is induced by TNF- or LPS on nonprofessional APC, such as fibroblasts (3, 6, 7, 8, 9). In vitro, ICOS costimulation increases T cell proliferation, and the production of Th1 cell and Th2 cell cytokines. However, ICOS costimulation has only limited effects on IL-2 production (2, 3). In a different set of experiments, blocking of the ICOS/B7RP-1 interaction reduced the production of Th2 cell cytokines, leaving Th1 cell cytokine production unimpaired (4, 5). Consistent with these findings, T cells from ICOS-deficient mice exhibit reduced IL-4 and IL-5 production, but normal or even increased IFN- production (10, 11, 12).

Results from different in vivo models point to ICOS as a regulator for Th2 responses. Blocking of ICOS signaling ameliorates the severity of disease in different Th2 cell-mediated inflammatory lung models (4, 13, 14). Interestingly, an ICOS blockade during the effector phase is superior to a blockade during the priming phase of Th2 cells in terms of preventing disease (13). This observation suggests that ICOS costimulation acts mainly on recently activated and effector T cells, but not on naive T cells, which is consistent with the absence of ICOS on naive T cells.

Although ICOS costimulation can enhance the production of Th1 cytokines in vitro, there is only limited evidence that ICOS signaling influences Th1 cell responses in vivo. During parasite infection of mice, blocking of ICOS costimulation reduces the production of IFN- with limited effects on the severity of disease, and the inhibition of ICOS signaling only marginally impairs Th1 cell responses to different viral pathogens (15, 16). In a Th1 cell-mediated experimental allergic encephalomyelitis (EAE) model, the obstruction of ICOS signaling prevents in vitro differentiation of Th1 cells to effector T cells that cause disease (17). In a different EAE model, ICOS blocking in vivo during the effector phase of EAE ameliorates disease, accompanied by reduced cellular infiltration into the brain and impaired IFN- and chemokine production (18). Remarkably, the inhibition of ICOS signaling prolongs the survival of allogeneic heart transplants (19).

After activation, CD8⁺ T cells express ICOS at a low density on their surface (5, 20). However, the blocking of ICOS signaling does not affect CD8⁺ T cell responses to different viral pathogens (16). Yet, there is evidence that ICOS signaling can influence CD8⁺ T cell responses. After treatment of mice with bacterial superantigens, inhibition of ICOS signaling diminishes CD8⁺ T cell proliferation (21). ICOS costimulation of CD8⁺ T cells in vitro promotes proliferation and cytokine production (20), and transfection of tumor cells with the ICOS ligand, B7RP-1, accelerates CD8⁺ T cell-mediated tumor rejection (20, 22).

Here we analyze the role of ICOS in the acquired immune response to the intracellular bacterium Listeria monocytogenes. Listeria Ags are presented via both the MHC class I and class II pathways. Consequently, L. monocytogenes infection induces a CD8⁺ T cell response and a Th1-polarized CD4⁺ T cell response (23). Both T cell populations are involved in the control of bacterial infection, and CD8⁺ T cells appear to be particularly important for protection against secondary infections (23).

Using ICOS-Ig fusion proteins, we demonstrate that blocking of ICOS signaling increases the susceptibility of mice against oral L. monocytogenes infection. ICOS-Ig-treated mice fail to mount a proper CD8⁺ T cell response and show diminished IFN- production by CD4⁺ and CD8⁺ T cells. Thus, ICOS cosignaling is crucial for the development of a protective immune response against an intracellular bacterial pathogen.

	Materials and Methods

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Abs and Ig fusion proteins

Anti-CD16/CD32 mAb (clone 2.4G2), anti-IFN- mAb (clone R4-6A2, IgG1), anti-CD4 mAb (clone YTS191.1), anti-CD8 mAb (clone YTS169), and anti-CD62L mAb (clone Mel-14) were purified from hybridoma supernatants and conjugated according to standard protocols. FITC- and the PE-conjugated rat-IgG1 isotype control mAb (clone R3-34) and PE-conjugated anti-IL-4 mAb (clone 11B11, rat IgG1) were purchased from BD PharMingen, San Diego, CA.

The construction and the purification of the mouse ICOS human IgG1 Fc fusion protein (ICOS-Ig) and the control IgG1 Fc protein (con-Ig) have been described previously (3).

To prepare the anti-ICOS mAb, 5-wk-old Lou rats (Harlan Sprague Dawley) received i.p. and s.c. injections at 4-wk intervals with 5 x 10⁶ murine ICOS-CHO transfected cells in PBS. Purified murine ICOS-Ig was used for the final i.v. boost before fusion. Splenocytes from these animals were fused with Y3-Ag1.2.3 rat myeloma cells (CRL 1631; American Type Culture Collection, Manassas, VA). Ten to 14 days postfusion, conditioned media from hybridoma-containing wells were screened by ELISA against both ICOS-Ig and con-Ig. Hybridomas of interest were subcloned by limiting dilution and tested further by flow cytometric analysis.

Bacteria and bacterial infection of mice

Listeria (strain EGD) were grown in tryptic soy broth to late log phase and were washed twice in PBS. The bacterial density was determined by the absorption at 600 nm, and the bacteria were appropriately diluted in PBS. Bacteria were applied to BALB/c mice in a total volume of 200 µl PBS by gastric intubation. Three to 4 h before infection and from then on every other day, mice received 200 µg ICOS-Ig or con-Ig (in 200 µl PBS i.p.). Experiments were conducted according to German animal protection law. To determine the bacterial burdens, spleens were homogenized in PBS, serial dilutions of homogenates were plated on tryptic soy broth agar plates, and colonies were counted after 24-h incubation at 37°C.

In vitro restimulation of spleen cells and flow cytometric determination of cytokines

Spleen cells (3 x 10⁶/well) were stimulated for 5 h with 10^-6 M of the peptide listeriolysin O_91–99 (LL0_91–99; GYKDGNEYI, Jerini Bio Tools, Berlin, Germany) or heat-killed Listeria (5 x 10⁷/ml). During the final 4 h of culture, 10 µg/ml brefeldin A was added. Cells were stained extracellularly with Cy5-conjugated anti-CD8 mAb or anti-CD4 mAb and intracellularly with FITC-conjugated anti-IFN- mAb and PE-conjugated anti-IL-4 mAb or the corresponding FITC- and PE-conjugated isotype control mAbs as described previously (24). For detection of ICOS expression, the cells were stained extracellularly with PE-conjugated anti-CD4 mAb or anti-CD8 mAb and intracellularly with FITC-conjugated anti-IFN- mAb. ICOS staining was performed extracellularly or intracellularly with the Cy5-conjugated anti-ICOS mAb. For staining controls, anti-ICOS mAb was incubated for 15 min with a 30-fold molar excess of ICOS-Ig before adding it to the cell samples.

Purification of cells and staining of cells with tetramers

Intraepithelial lymphocytes and lamina propria lymphocytes from the small intestine and lymphocytes from the liver were isolated using a 40/70% Percoll gradient as previously described (25). Cells were stained with Cy5-conjugated anti-CD8 mAb, FITC-conjugated anti-CD62L mAb, and PE-conjugated MHC class I LLO_91–99 tetramers (24) or with FITC-conjugated anti-CD8 mAb, Cy5-conjugated anti-ICOS mAb, and PE-conjugated tetramers. For staining controls, the anti-ICOS mAb was incubated for 15 min with a 30-fold molar excess of ICOS-Ig before adding it to the samples. Directly before analysis of cells, propidium iodide was added.

Statistical analysis

The statistical significance of the results was determined with the statistics program included in PRISM software (GraphPad, San Diego, CA). Bacterial titers were analyzed with the Mann-Whitney test, and frequencies and numbers of tetramer-positive or cytokine-expressing cells were determined by unpaired Student’s t test. A value of p < 0.05 was considered a statistically significant difference.

	Results

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Blocking of ICOS cosignaling increases susceptibility to L. monocytogenes infection

Natural infection with L. monocytogenes originates from the consumption of contaminated food. Therefore, BALB/c mice were orally infected with 10⁹ Listeria, a dose that is well tolerated by BALB/c mice. ICOS signaling was blocked by repeated injections of a soluble ICOS-Ig fusion protein. This treatment had profound effects on the course of infection. By day 7, 15 of the 25 ICOS-Ig-treated mice (in five independent experiments) had succumbed to the oral L. monocytogenes infection, and several of the surviving mice were moribund. In contrast, none of the con-Ig-treated mice succumbed to infection (of 21 mice), and none of these mice showed overt signs of disease. On day 7, the surviving ICOS-Ig-treated mice had bacterial abscesses in the spleen and liver (data not shown), and their spleens contained high numbers of Listeria. Fig. 1 shows the result from an experiment in which four of five ICOS-Ig-treated mice survived the infection for 7 days. At this time point, the con-Ig-treated mice showed either low bacterial titers or had completely cleared Listeria from the spleen.

View larger version (11K): [in this window] [in a new window]   FIGURE 1. ICOS-Ig treatment increases L. monocytogenes titers in spleens of infected mice. BALB/c mice were treated i.p. with 200 µg of either ICOS-Ig or con-Ig on days 0, 2, 4, and 6. Three hours after the first injection, mice were infected orally with 109 Listeria. On day 7, bacterial titers were determined. The statistical difference between titers from ICOS-Ig- and con-Ig-treated mice was determined with the Mann-Whitney test.

In BALB/c mice, the CD8⁺ T cell response to Listeria is concentrated on a few immunodominant epitopes. The most prominent of these listerial epitopes is derived from the secreted pore-forming protein, LLO (aa 91–99; LLO_91–99) (24). Therefore, we used LLO_91–99-loaded MHC class I tetramers to analyze the specific CD8⁺ T cell response to L. monocytogenes infection in ICOS-Ig-treated animals. Fig. 2 shows representative results for LLO_91–99 tetramer and CD62L staining of CD8⁺ T cells isolated from different organs. CD62L is a surface molecule of CD8⁺ T cells that is down-regulated in spleen and liver following T cell activation. The situation is different in the intestinal mucosa, where the vast majority of CD8⁺ T cells typically express low levels of CD62L. Consistent with published results (26, 27), we observed high frequencies and numbers of LLO_91–99-specific CD8⁺ T cells in spleen, liver, and lamina propria and lower frequencies in intestinal epithelium of con-Ig-treated mice on day 7 of infection (Figs. 2 and 3). As expected, the vast majority of these cells were CD62L^low (Fig. 2). In contrast to the con-Ig treatment, the ICOS-Ig treatment markedly diminished the frequencies and numbers of LLO_91–99-specific CD8⁺ T cells in spleens and livers of infected mice. This result was observed in all animals regardless of whether the mice were moribund (of the 10 ICOS-Ig treated mice that survived infection, nine were individually analyzed in four independent experiments with similar results). The frequencies and numbers of LLO_91–99-specific CD8⁺ T cells were not reduced in the intestinal mucosa of ICOS-Ig-treated mice. Although some ICOS-Ig-treated mice demonstrated a diminished response, there was no significant difference when the group of ICOS-Ig-treated mice was compared with the con-Ig-treated animals (data not shown).

View larger version (55K): [in this window] [in a new window]   FIGURE 2. CD8+ T cell response in L. monocytogenes-infected mice after ICOS-Ig treatment. BALB/c mice were treated i.p. with 200 µg of either ICOS-Ig or con-Ig on days 0, 2, 4, and 6. Three hours after the first injection, mice were infected orally with 109 Listeria. On day 7, lymphocytes from the indicated organs were purified, stained, and analyzed by flow cytometry. The figures show live-gated CD8+ T cells. The x- and y-axes are given in logarithmic scale (log10). Numbers represent the percentage of live CD8+ T cells. LPL, lamina propria lymphocytes; IEL, intraepithelial lymphocytes.

View larger version (27K): [in this window] [in a new window]   FIGURE 3. CD8+ T cell response in L. monocytogenes-infected mice after ICOS-Ig treatment. BALB/c mice were treated as described in Fig. 2. On day 7, lymphocytes isolated from the indicated organs were counted and analyzed as described in Fig. 2. Total cell numbers were calculated from the numbers of recovered cells per tissue and the percentage of LLO91–99 tetramer+ CD62L- CD8+ T cells. Bars represent the mean ± SD of an experiment with three (con-Ig) or two (ICOS-Ig) individually analyzed mice per group and are representative of four independent experiments (note the different scales of the y-axis). *, p < 0.05. NS, not significant (determined with Student’s t test); LPL, lamina propria lymphocytes; IEL, intraepithelial lymphocytes.

ICOS-Ig treatment reduces frequencies of IFN--producing CD4⁺ and CD8⁺ T cells

Spleen cells from infected mice were cultured with the peptide LLO_91–99 and then analyzed by intracellular cytokine staining for the expression of IFN- and IL-4 (Fig. 4). Without peptide restimulation, we observed only marginal frequencies of IFN--producing CD8⁺ T cells in spleens from infected mice. The incubation with LLO_91–99 resulted in frequencies of 0.8% IFN-⁺ CD8⁺ T cells in the spleens from con-Ig-treated mice. In contrast, ICOS-Ig treatment markedly reduced the frequencies of CD8⁺ T cells that responded to LLO_91–99 with IFN- production.

View larger version (32K): [in this window] [in a new window]   FIGURE 4. Cytokine production by T cells from L. monocytogenes mice after ICOS-Ig treatment. BALB/c mice were treated i.p. with 200 µg of either ICOS-Ig or con-Ig on days 0, 2, 4, and 6. Three hours after the first injection, mice were infected orally with 109 Listeria. On day 7, spleen cells were restimulated ex vivo for 5 h with LLO91–99 or heat-killed Listeria (HKL) or were left untreated. Frequencies of IFN-- and IL-4-producing cells were determined by flow cytometry. Intracellular staining with FITC- and PE-conjugated isotype control mAbs always resulted in <0.05% positive cells (not shown). The figures show representative results for CD4- or CD8-gated cells, and numbers represent the percentage calculated for CD4+ or CD8+ T cells. The x- and y-axes are logarithmic scales (log10). Numbers below the figures give the mean percentage ± SD for IFN-+ cells from an experiment with three (con-Ig) or two (ICOS-Ig) individually analyzed mice per group and are representative of three independent experiments. The percentages of con-Ig- and ICOS-Ig-treated mice were compared with Student’s t test (*, p < 0.05; NS, not significant).

ICOS expression on Listeria-specific CD4⁺ and CD8⁺ T cells

Several reports indicate that ICOS is not expressed on resting CD8⁺ T cells and is only slowly up-regulated after activation (3, 5, 20). It was therefore important to determine whether Listeria-specific CD8⁺ T cells express ICOS. Direct ex vivo costaining of CD8⁺ T cells with LLO_91–99 tetramers and anti-ICOS mAb revealed that a significant population of these cells expressed ICOS on the surface on day 8 of infection (Fig. 5). Cells were also analyzed after in vitro culture for 5 h with the peptide LLO_91–99. IFN-⁺ CD8⁺ T cells hardly expressed any ICOS on the surface, but intracellular staining revealed low, but distinct, expression in these cells.

View larger version (37K): [in this window] [in a new window]   FIGURE 5. ICOS expression on Listeria-specific T cells. BALB/c mice were infected orally with 109 Listeria. After 8 days, spleen cells were analyzed for the expression of ICOS. Top row, Cells were stained with FITC-conjugated anti-CD8 mAb, Cy5-conjugated anti-ICOS mAb, and PE-labeled LLO91–99 tetramers. In control samples, the anti-ICOS mAb was preincubated with a 30-fold molar excess of ICOS-Ig before cell staining. The figures show live-gated CD8+ T cells. Lower rows, Cells were incubated for 5 h with either LLO91–99 or heat-killed Listeria (HKL). Cells were extracellularly stained with PE-conjugated anti-CD4 mAb or anti-CD8 mAb and intracellularly stained with FITC-conjugated anti-IFN- mAb. Staining with Cy5-conjugated anti-ICOS mAb was performed either extracellularly (extra) or intracellularly (intra). In controls the anti-ICOS mAb was blocked by incubation with an excess of ICOS-Ig. Dot plots display CD4+ T cells after incubation with heat-killed Listeria or CD8+ T cells after incubation with LLO91–99. Histograms show an overlay of control (gray field) and ICOS staining (black line) for LLO91–99 tetramer+ or IFN-+ T cells. The x- and y-axes are logarithmic scales (log10). The experiment shown is representative of three independent experiments.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Our studies demonstrate a crucial role of ICOS signaling in the development of the protective CD8⁺ T cell response against oral L. monocytogenes infection. Blocking of ICOS signaling in vivo impaired the generation of Listeria-specific CD8⁺ T cells and Listeria-specific CD4⁺ Th1 cells, as determined by tetramer and intracellular cytokine staining. It has been suggested that ICOS signaling has only a limited influence on T cell priming, but affects the function of recently activated and effector T cells (4, 13, 15). We did not address the T cell effector functions, but our experiments demonstrate that blocking of ICOS signaling affects priming and/or expansion of the Listeria-specific CD4⁺ and CD8⁺ T cell populations. The highly diminished T cell response in ICOS-Ig-treated mice also increased the susceptibility to oral L. monocytogenes infection.

A prerequisite for direct effects of ICOS on Listeria-specific T cells is its surface expression on these cells. A significant population of Listeria-specific CD8⁺ T cells expressed ICOS on the surface, although at a relatively low level. After the peptide incubation, there was no or only weak surface staining, but distinct intracellular ICOS staining was observed in the responding T cells. We assume that the intracellular enrichment of ICOS was due to the brefeldin A incubation, which hindered the transport of ICOS to the cell surface. However, we cannot exclude that ICOS expression after activation is a dynamic process, and that intracellular stores for the ICOS molecule exist, as described for the related CTLA-4 molecule (28). Overall, our results demonstrate that subpopulations of Listeria-specific CD8⁺ T cells and CD4⁺ Th1 cells either express ICOS or rapidly produce the molecule following Ag encounter.

ICOS-Ig treatment reduced CD8⁺ T cell frequencies in spleens and livers, but not in intestinal mucosa, implying tissue-specific requirements for ICOS costimulation. This observation is different from the situation in CD28-deficient mice, where the CD8⁺ T cell response after oral infection was highly impaired in all organs analyzed (H.-W. Mittrücker, unpublished observations). For other cosignals, tissue-specific requirements have been reported (27). Following L. monocytogenes infection, the CD8⁺ T cell response is independent from CD4⁺ T cell help and the CD40/CD40L interaction in the spleen, but requires these signals in the intestinal mucosa (27). In our infection model the requirement for ICOS signaling showed an inverse pattern, with a high dependency in spleen and liver and a low or even absent influence in intestinal mucosa. It is possible that tissue-specific requirements are due to differential expression levels of the ICOS ligand, B7RP-1, in these tissues. However, it is also possible that the ICOS-Ig protein fails to penetrate the intestinal mucosa in sufficiently high concentrations to block ICOS/B7RP-1 interactions in this tissue.

To date, the role of ICOS in the development of CD8⁺ T cell responses and/or CD4⁺ Th1 cell responses in infection has been studied in two models (15, 16). After infection with Leishmania mexicana, ICOS-deficient mice demonstrated impaired Ab production, and CD4⁺ T cells from infected mice secreted diminished amounts of cytokines. The production of both IgG1 and IgG2a as well as the secretion of both IL-4 and IFN- were impaired, indicating that ICOS signaling was involved in the regulation of both the Th2 and Th1 responses against this pathogen (15). Comparable results were observed after infection of mice with Nippostrongylus brasiliensis (16). Treatment with an ICOS-Ig fusion protein reduced the production of Th1 and Th2 cytokines. However, IFN- production by CD8⁺ T cells was not affected. The ICOS-Ig fusion protein was also used to analyze T cell responses against lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus (16). During LCMV infection, the ICOS-Ig treatment had only marginal effects on the Th1 cell response and no influence on the CD8⁺ T cell response. The Th1 cell response against vesicular stomatitis virus was more sensitive to ICOS-Ig treatment, but again the CD8⁺ T cell response was not impaired (16). Currently, we have no explanation for the strong impairment of the CD8⁺ T cell responses in Listeria infection compared with the limited effect on CD8⁺ T cells in other infection models. This discrepancy is reminiscent of CD28 costimulation, which influences CD8⁺ T cell responses against L. monocytogenes but not against certain virus strains (reviewed in Ref. 24).

In conclusion, this report describes a novel role of ICOS in the regulation of protective CD8⁺ T cell responses in a biologically relevant model of a food-borne infection with a bacterial pathogen.

	Acknowledgments

 
We thank Dr. Robert Hurwitz for assistance in the preparation of tetramers; Dr. Kerstin Bonhagen for help with the FACS staining; Manuela Stäber for purification and labeling of Abs; John S. Whoriskey and Thomas Horan for construction, expression, and purification of fusion proteins; and Dr. Brenda G. Yoshinaga for help in editing of the manuscript.

	Footnotes

 
¹ M.K. was supported by the Graduiertenkolleg 276/2, and this work will be part of his Ph.D. thesis.

² Address correspondence and reprint requests to Dr. Hans-Willi Mittrücker, Max Planck Institute for Infection Biology, Schumannstrasse 20/21, 10117 Berlin, Germany. E-mail: mittruecker{at}mpiib-berlin.mpg.de

³ Abbreviations used in this paper: ICOS, inducible costimulator; EAE, experimental allergic encephalomyelitis; LCMV, lymphocytic choriomeningitis virus; LLO, listeriolysin O.

Received for publication June 17, 2002. Accepted for publication September 12, 2002.

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