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Infection and Immunity, November 2003, p. 6641-6647, Vol. 71, No. 11
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.11.6641-6647.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Mice Deficient in Nuclear Factor of Activated T-Cell Transcription Factor c2 Mount Increased Th2 Responses after Infection with Nippostrongylus brasiliensis and Decreased Th1 Responses after Mycobacterial Infection

Klaus J. Erb,1* Thomas Twardzik,2 Alois Palmetshofer,2 Gisela Wohlleben,1 Ursula Tatsch,1 and Edgar Serfling2*

Research Center for Infectious Diseases,1 Department of Molecular Pathology, Institute of Pathology, University of Wuerzburg, D-97080 Wuerzburg, Germany2

Received 27 January 2003/ Returned for modification 1 April 2003/ Accepted 4 August 2003


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ABSTRACT
 
Infection of nuclear factor of activated T-cell transcription factor c2 (NFATc2)-deficient mice with the helminth Nippostrongylus brasiliensis led to a distinct increase in interleukin-4 (IL-4) and IL-5 protein synthesis by lymph node and spleen cells and to elevated serum immunoglobulin E (IgE) levels in comparison to those seen with infected control mice. While IL-4, IL-5, and IL-13 mRNA expression was also enhanced in lymph node cells from the lungs of infected NFATc2-/- mice, the number of T cells secreting Th2-type lymphokines remained the same in mice infected with N. brasiliensis. In contrast, lymphocytes from NFATc2-deficient mice infected with Mycobacterium bovis BCG secreted less gamma interferon than lymphocytes from infected control mice. These findings indicate that NFATc2 is an activator of Th1 responses and a suppressor of Th2 responses in vivo.


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TEXT
 
The four genuine members of the family of nuclear factor of activated T-cell transcription factors (NFAT), NFATc1, NFATc2, NFATc3, and NFATc4, share a conserved DNA binding domain of approximately 300 amino acids, the Rel similarity domain. Their nuclear translocation and activity is controlled by the Ca2+-calmodulin-dependent phosphatase calcineurin that binds to and dephosphorylates the N-terminal portion of NFAT proteins upon T-cell activation (12, 15). In peripheral T lymphocytes, NFATc1 and NFATc2 are the most abundant NFAT factors. They are involved in the activation of T cells by controlling the transcription of interleukin-2 (IL-2) and further lymphokine promoters. However, NFATc1 and NFATc2 also bind to numerous other promoters, such as the Fas ligand promoter (4, 8), and therefore also control apoptosis and further important processes in the life cycle of a T cell (12, 15).

Due to the binding of NFATc1 and NFATc2 to the promoters of the gamma interferon (IFN-{gamma}), IL-4, and IL-5 genes (i.e., the promoters of genes that are active either in Th1 or in Th2 cells), it has been assumed that NFATc1 and NFATc2 play an important role in driving naive T cells to effector Th1 and Th2 cells. Indeed, NFATc1-deficient (-/-) lymphocytes showed a significant decrease in Th2 responses (11, 18), and T cells doubly deficient for NFATc1 and NFATc2 were additionally defective in the synthesis of the Th1-type lymphokines IFN-{gamma} and IL-2 (9). In contrast, three lines of NFATc2-/- mice (3, 14, 17) exhibited divergent patterns of synthesized lymphokines. Whereas in all three lines no distinct decrease in Th1-type lymphokines was detected, T cells from two NFATc2-/- lines synthesized markedly more Th2-type RNAs or secreted more IL-4 than wild-type T cells (3, 11). In contrast, the third line showed a decrease in IL-4 production (14), at least after primary immune stimulation. These conflicting data prompted us to infect NFATc2-/- mice (backbred seven generations on the C57BL/6 background) (13, 14) and 5- to 8-week-old age-matched C57BL/6 control mice with a mouse-adapted strain of the helminth Nippostrongylus brasiliensis or with the Mycobacterium bovis BCG strain, which induces strong Th2 or Th1 responses in vivo, respectively, as described previously (2). All mice were kept under specific-pathogen-free conditions.

Figure 1 shows that prior to infection, T cells from the mediastinal lymph nodes (MLN), mesenteric lymph nodes (MESLN), and spleens of both types of mice secreted no or only very low amounts of IL-4 and IL-5 after in vitro stimulation with anti-CD3 ({alpha}-CD3) antibodies (Abs) and IL-2 (for descriptions of cell preparations and enzyme-linked immunosorbent assays [ELISAs], see reference 2). At 10 days following infection, in contrast, T cells from control mice or NFATc2-/- mice secreted large amounts of IL-4 and IL-5 after restimulation. Most importantly, T cells from infected NFATc2-/- mice secreted significantly more IL-4 and IL-5 than T cells from infected control mice. This clearly indicates that NFATc2 is involved in the downregulation not only of allergen-specific responses (16) but also of Th2 responses induced after infection.



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  		FIG. 1. NFATc2 deficiency leads to an increase in Th2 responses in mice infected with the helminth N. brasiliensis (Nippo). (A) NFATc2-/- and control mice were infected with N. brasiliensis for 10 days. MLN, MESLN, and spleen cells were stimulated with {alpha}-CD3 plus IL-2, and IL-4, IL-5, and IFN-{gamma} secretion levels were determined by ELISA. The amounts of cytokines secreted by T cells from individual mice are shown (due to the low numbers of cells present in MLN of noninfected mice, the MLN of five mice per group were pooled). (B) Total amounts ofIL-4-producing CD4+ T cells per organ or per milliliter of BAL fluid as determined by intracellular FACS staining. (C and D) NFATc2-/- mice showed increased serum IgE and IgG1 levels. Levels of serum IgE and IgG1 from noninfected control mice and NFATc2-/- mice or mice infected with N. brasiliensis were determined by ELISA. The experiments using MLN cells from infected NFATc2-/- and control mice and the experiments represented by panels C and D were repeated once with similar results. *, P < 0.05; **, P < 0.01. Student's t test was used for the MLN data presented in panel A; for all other data, ANOVA was used. Wt, wild type.

To determine whether the enhanced IL-4 and IL-5 production was due to an increase in the amount of Th2 cells generated during infection, bronchoalveolar lavage (BAL) fluid, lymph nodes, and spleen cells from infected mice were stimulated with a combination of tetradecanoyl phorbol acetate (TPA) and ionomycin and brefeldin A, fixed, and assayed for intracellular IL-4 staining as described previously (7). Interestingly, we found that the percentages and total numbers of CD4+ T cells producing IL-4 (Fig. 1B) in most organs showed only a slight increase for NFATc2-/- mice compared to those seen with control mice (24.2 x 104 ± 5 x 104 BAL control versus 24.1 x 104 ± 8.4 x 104 BAL-NFATc2-/- CD4+ T cells; 5.8 x 104 ± 2.3 x 104 MLN control versus 8.2 x 104 ± 2 x 104 MLN-NFATc2-/- CD4+ T cells; 3.7 x 104 ± 1.7 x 104 MESLN control versus 3.8 x 104 ± 2 x 104 MESLN-NFATc2-/- CD4+ T cells; and 3 x 104 ± 1.2 x 104 spleen control versus 4.4 x 104 ± 1.6 x 104 spleen-NFATc2-/- CD4+ T cells [mean ± standard deviation values for six mice per group]). This suggests that NFATc2 deficiency does not lead to an increase in the numbers of Th2 lymphocytes but that NFATc2-/- T cells secrete more IL-4 and IL-5 at the single-cell level. Supporting this view is the finding that the total numbers of cells present in the MLN, MESLN, and spleen were also not increased in the NFATc2-/- mice in comparison to those in control animals after infection (data not shown). However, Fig. 2 shows that the intensity of the intracellular fluorescence-activated cell sorter (FACS) staining for IL-4 produced by CD4+ T cells from NFATc2-deficient mice was also not enhanced. The discrepancy between this finding and the ELISA data is most likely due to the different stimuli used (TPA-ionomycin versus anti-CD3-IL-2) or the different stimulation times used (6 h versus 48 h).



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  		FIG. 2. CD4+ T cells from NFATc2-/- mice infected with N. brasiliensis (Nippo) show no enhanced IL-4 production, as measured by intracellular FACS staining. NFATc2-/- and control mice were infected with N. brasiliensis. At 10 days after infection, single-cell suspensions of MLN, MESLN, and spleen were prepared and BALs were performed. The cells were stimulated in vitro with phorbol ester and calcium ionophore, fixed, and stained for the expression of CD4 and IL-4 by incubating the cells with anti-CD4-fluorescein isothiocyanate monoclonal Ab (MAb) in combination with a phycoerythrin (PE)-labeled anti-IL-4 MAb. Specificity of antibody binding was controlled by staining with irrelevant isotype-matched control antibodies (<0.1%) (data not shown). The results of FACS staining gated on CD4+ T cells are shown (results are representative of six mice per group). The percentages of CD4+ T cells producing IL-4 are indicated. The intensity of the IL-4 staining is indicated in the histograms. Wt, wild type; FL1-H, fluorescent channel 1 height; FL2-H, fluorescent channel 2 height.

Next we investigated whether the increase in synthesis of Th2-type lymphokines which we measured after in vitro stimulation of T cells from infected NFATc2-/- mice correlated with increased Th2-dependent immune responses in vivo by determining immunoglobulin G1 (IgG1) and IgE serum levels as described previously (1). Figure 1C shows that NFATc2 deficiency led to a significant increase in total serum IgE levels in infected mice, while IgG1 levels were slightly elevated (Fig. 1D). Interestingly, uninfected NFATc2-/- mice also showed increased IgG1 and, to a lesser degree, IgE serum levels. Since the Ig isotype switch to IgE is to a great extent IL-4 dependent, these data indicate that Th2 cells in NFATc2-/- mice secreted more IL-4 during infection with N. brasiliensis. However, levels of airway eosinophilia, a further hallmark of an N. brasiliensis-induced Th2 response, were not found to be increased in infected NFATc2-/- mice in comparison to those seen with control mice infected with the helminths. Similarly, the relative numbers of macrophages, lymphocytes, and neutrophils were found to be similar in airways of infected NFATc2-/- and control mice (data not shown).

We also investigated whether NFATc2 deficiency affects RNA synthesis of lymphokines upon N. brasiliensis infection. As shown in Fig. 3, RNase protection analysis (the kit used was purchased from Pharmingen) revealed that in MLN cells infected with N. brasiliensis and stimulated for 24 h in vitro with anti-CD3 and IL-2, NFATc2 deficiency led to higher IL-4, IL-5, and IL-13 but not IL-2 or IFN-{gamma} mRNA levels. Whereas unstimulated MLN cells from infected control or NFATc2-/- mice produced no or very few cytokine-specific mRNAs (data not shown), stimulation with anti-CD3 plus IL-2 for 24 h resulted in an almost twofold increase in Th2-type lymphokine RNAs, although the effect (as assessed by analysis of variance [ANOVA]) was not significant. No increase or a very weak increase was detected for IL-2, IL-10, and IFN-{gamma} mRNA levels in the MLN cells from NFATc2-/- mice. This suggests that the potential negative effect of the presence of NFATc2 on transcription during helminth-induced immune responses might be limited to the type 2 lymphokine genes.



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  		FIG. 3. MLN cells from NFATc2-/- mice infected with N. brasiliensis showed increased IL-4, IL-5, and IL-13 RNA levels after in vitro stimulation. NFATc2-/- (-/-) and control (+/+) mice were infected with N. brasiliensis. At 10 days after infection, MLN cells were isolated and stimulated in vitro with anti-CD3 in the presence of 200 U of IL-2/ml for 14 or 24 h. RNA was prepared at 14 or 24 h after stimulation. (A) Cytokine mRNA levels were determined by RNase protection analysis. Representative RNA samples from an analysis of 10 NFATc2-/- and 7 control mice are shown (the MLN of 2 to 3 mice were pooled before stimulation [a total of five NFATc2-/- and three control samples were analyzed]). (B) Phosphorimaging analysis of mRNA data obtained from RNase protection analysis. Data are average values of means ± standard errors of the means from five samples derived from NFATc2-/- mice and three samples obtained from control mice (the results shown in panel B were normalized to the arithmetic average value of the signal intensities of both L32 and GAPDH [glyceraldehyde-3-phosphate dehydrogenase]). WT, wild type; KO, knockout.

The data discussed above clearly indicated that NFATc2 was responsible for the downmodulation of Th2 responses. Next we analyzed whether NFATc2 deficiency also has an influence on the development of Th1 responses in vivo. For this purpose NFATc2-/- and control mice were intranasally (i.n.) inoculated with 106 CFU of BCG (strain Copenhagen) as described previously (1). At 14 days later, MLN cells were stimulated with purified protein derivative (PPD) from M. tuberculosis or with a combination of {alpha}-CD3 Ab and IL-2. Preparation and stimulation of cells and the ELISA for IL-4, IL-5, and IFN-{gamma} were performed as described previously (1). Figure 4A shows that the amount of IFN-{gamma} secreted by T cells from NFATc2-/- mice was significantly lower than that seen with T cells from control mice. In contrast to the ELISA results, RNase protection analysis of the RNA isolated from the MLN cells from mice infected with BCG i.n. for 14 days revealed that when activated in vitro for 14 or 24 h with anti-CD3 and IL-2 or for 24 h with PPD, the MLN cells from NFATc2-/- mice did not produce significantly reduced levels of IFN-{gamma} mRNA in comparison to MLN cells from control mice (data not shown). This suggests that although less IFN-{gamma} was secreted by NFATc2-deficient T cells, this was not reflected by reduced mRNA levels. A similar result was found when MLN cells from helminth-infected mice were analyzed (Fig. 1 and 3). Furthermore, Fig. 5 shows that although the MLN of NFATc2-/- mice infected with BCG contained fewer CD4+ T cells secreting IFN-{gamma} (as detected by intracellular FACS staining after in vitro stimulation with TPA and ionomycin) than the MLN of control mice, this difference was not significant (11.68 x 104 ± 4 x 104 CD4+ T cells for control mice versus 7.9 x104 ± 4 x104 CD4+ T cells for NFATc2-/- mice [means ± standard errors of the means by Student's t test for seven mice per group]). Taken together, these results indicated that although MLN cells from NFATc2-deficient mice infected with BCG secreted less IFN-{gamma} and fewer CD4+ cells produced IFN-{gamma} than cells from control mice, this effect was not detected on the mRNA level.



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  		FIG. 4. MLN cells from NFATc2-/- mice infected with BCG showed a reduction in IFN-{gamma} but not in IL-5 secretion in comparison to MLN cells from control mice. NFATc2-/- and control mice were infected with BCG, and 14 days after infection single-cell suspensions from total MLN cells were stimulated in vitro for 48 h on {alpha}-CD3-bound plates in the presence of IL-2 or with PPD (20 µg/ml). The levels of IFN-{gamma} (A) and IL-5 (B) present in the supernatants of cells from individual mice were determined by ELISA. The experiment was repeated once with similar results. *, P < 0.05 (by ANOVA). Wt, wild type.



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  		FIG. 5. Numbers of CD4+ T cells producing IFN-{gamma} in the MLN of control and NFATc2-/- mice infected with BCG. NFATc2-/- mice and control mice were infected i.n. with 2 x 106 CFU of BCG. At 14 days after infection, single-cell suspensions of MLN were prepared. Cells were stimulated in vitro (as described in the legend for Fig. 2), and intracellular staining was performed by incubating the cells with anti-CD4-FITC MAb in combination with a phosphatidylethanolamine (PE)-labeled anti-IFN-{gamma} MAb. Wt, wild type. (A) Results representing FACS staining gated on CD4+ T cells are shown (results are representative of seven mice per group). The percentages of CD4+ T cells producing IFN-{gamma} are also indicated. Positive staining was controlled using isotype control MAb. FL1-H, fluorescent channel 1 height; FL2-H, fluorescent channel 2 height. (B) The total amounts of IFN-{gamma}-producing CD4+ (CD4+ IFN-{gamma}+) T cells per MLN of seven individual mice per group (as determined by intracellular FACS staining) are shown.

We also analyzed whether NFATc2-/- mice infected with BCG mounted increased Th2 responses after infection. Figure 4B shows that after the MLN cells were stimulated with anti-CD3-IL-2 or PPD in vitro, the amounts of IL-5 were similar in both groups of mice. IL-4 could not be detected in any of the cultures. There was also no difference in the amounts of IL-4, IL-5, or IL-13 mRNA produced by MLN cells from the two groups of mice infected with BCG for 14 days after the in vitro stimulation with PPD (24 h) or anti-CD3/IL-2 (14 and 24 h) (as measured by RNase protection assays [data not shown]). However, total IgE levels did increase in the serum of NFAT2c-deficient mice infected for 14 days with BCG in comparison to the levels seen with infected control mice (<0.02 µg/ml for uninfected control mice versus 0.4 ± 0.15 µg/ml for infected control mice and 0.1 ± 0.07 µg/ml for uninfected NFATc2-/- mice versus 3.0 ± 2 µg/ml for infected NFATc2-/- mice [mean values for five to nine mice/group]; P < 0.05 [by ANOVA] in the comparisons of IgE levels in infected control mice to the levels seen in infected NFATc2-/- mice). Interestingly, total IgG1 levels in the serum did not differ for control mice or NFATc2-/- mice infected with BCG (data not shown). We also attempted to measure PPD-specific IgG1 and IgE serum levels (by coating ELISA plates with PPD and incubating with serum from infected or noninfected mice). However, we were not able to detect PPD-specific Ig in the serum of any of the BCG-infected mice at levels above those seen with nonspecific staining using serum from uninfected mice. Airway eosinophilia was also not detected in the BAL fluid of control or NFATc2-/- mice infected with BCG. These findings indicate that NFATc2 deficiency leads to decreased Th1 responses in vivo after infection with BCG. However, although the Th1 response after BCG infection was reduced this did not result in a significant reduction of bacterial clearance from the lungs of NFATc2-/- mice (results not shown). Furthermore, with the exception of increased IgE levels, Th2 responses were not increased after infection with BCG.

The experimental findings presented here indicate that NFATc2 deficiency results in a decrease in Th1 responses (i.e., a decrease in IFN-{gamma} production) and in an increase in Th2 responses (i.e., an increase in IL-4 and IL-5 production and higher IgE levels after infection). These results extend and support the findings of a number of studies using three different NFATc2-deficient mouse lines (3, 13, 14, 17) and suggesting that NFATc2 exerts contrasting effects on the generation of Th1 and Th2 cells. While it had been expected that NFATc2 would promote Th1 responses (i.e., by controlling the IFN-{gamma} promoter) (5), the suppression of Th2 responses by NFATc2 was an unexpected finding. The observation that NFATc2 deficiency impairs very early IL-4 transcription (3, 14) while strongly enhancing IL-4 expression and additional Th2 responses at later stages (3, 6, 16) suggests that NFATc2 (and NFATc3) (10) controls the synthesis of one (or several) repressor(s) of Th2 cell development. The existence of such a repressor(s) remains to be shown. However, we cannot completely rule out that the increase in Th2 responses observed with the NFATc2-deficient mice might have been due to decreased IFN-{gamma} production or to other not-yet-defined mechanisms.


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ACKNOWLEDGMENTS
 
This work was supported by the BMBF, the Bavarian Ministry of Science and Art, the DFG, SFB 465 (Würzburg), SFB 466 (Erlangen), and Forschergruppe FOR 303 (Würzburg) and by the Wilhelm-Sander-Stiftung.


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FOOTNOTES
 
* Corresponding author. Mailing address for K. J. Erb: Research Center for Infectious Diseases, Roentgenring 11, D-97070 Wuerzburg, Germany. Phone: 49 931 31 21 74. Fax: 49-931 31 25 78. E-mail: klaus.erb{at}mail.uni-wuerzburg.de Mailing address for E. Serfling: Department of Molecular Pathology, Institute of Pathology, Josef-Schneider-Str. 2, D-97080 Wuerzburg, Germany. Phone: 49 931 201 474 31. Fax: 49 931 201 471 31. E-mail: path015{at}mail.uni-wuerzburg.de. Back

Editor: J. M. Mansfield


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Infection and Immunity, November 2003, p. 6641-6647, Vol. 71, No. 11
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.11.6641-6647.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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