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Infection and Immunity, December 2005, p. 8437-8441, Vol. 73, No. 12
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.12.8437-8441.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Neutralization of Tumor Necrosis Factor Alpha Suppresses Antigen-Specific Type 1 Cytokine Responses and Reverses the Inhibition of Mycobacterial Survival in Cocultures of Immune Guinea Pig T Lymphocytes and Infected Macrophages

Hyosun Cho* and David N. McMurray

Department of Microbial and Molecular Pathogenesis, The Texas A&M University System Health Science Center, College Station, Texas 77843-1114

Received 13 July 2005/ Returned for modification 27 August 2005/ Accepted 18 September 2005


   ABSTRACT
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Neutralization of tumor necrosis factor alpha (TNF-{alpha}) significantly down-regulated antigen-induced lymphoproliferation and the expression of interleukin-12 p40 and gamma interferon mRNA and enhanced the viability of intracellular attenuated and virulent mycobacteria in cocultures of immune T cells and macrophages obtained from Mycobacterium bovis BCG-vaccinated guinea pigs. This suggests the crucial role of TNF-{alpha} in the activation of a type 1 T-cell response against Mycobacterium tuberculosis infection.


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The outcome of the interaction between host and Mycobacterium tuberculosis depends on reciprocal immune activation between infected macrophages and antigen-specific CD4+ T cells (5). Upon activation, CD4+ T cells differentiate into at least two functionally distinct effector subsets. Th1 cells are essential for resistance against M. tuberculosis (10). Gamma interferon (IFN-{gamma}) and interleukin-12 (IL-12) are considered to be the prototypical Th1-type cytokines (11). IFN-{gamma} is a key mediator of macrophage activation (27). In humans, a mutation in an IFN-{gamma} receptor was linked to a unique susceptibility to mycobacterial infection (16). IL-12 is required for the induction of Th1 differentiation (26) and has been shown to be crucial to the development of protective immunity against tuberculosis in humans (12). Tumor necrosis factor alpha (TNF-{alpha}) is also known to be essential for generating and maintaining protective immunity to mycobacterial infection. It has been shown to be indispensable for the colocalization of lymphocytes and macrophages within granulomas (4), and endogenous TNF-{alpha} production by mycobacterium-infected macrophages contributes to mycobacterial killing (6, 23). The guinea pig is considered to be one of best small animal models of tuberculosis because of the remarkable similarities between this model and humans, e.g., essentially identical granulomatous and hypersensitivity responses, heightened susceptibility to low-dose pulmonary infection with M. tuberculosis, and the ability to be protected against disease by vaccination with Mycobacterium bovis BCG (2, 17, 18). In our previous studies, we reported that BCG vaccination increased bioactive TNF-{alpha} responses in guinea pig leukocyte populations infected with mycobacteria in vitro (15). Recently, recombinant guinea pig TNF-{alpha} (rgpTNF-{alpha}) was shown to up-regulate IL-12 p40 mRNA expression in guinea pig macrophage populations (7) and to induce T-cell activation through enhancing the proliferation and expression of IL-12 p40 and IFN-{gamma} in splenocytes from BCG-vaccinated guinea pigs (submitted for publication). In this study, we investigated the impact of neutralizing endogenous TNF-{alpha} in a coculture system which attempts to model the cellular interaction between purified populations of immune T cells from BCG-vaccinated guinea pigs and macrophages infected with M. tuberculosis.

Different numbers of peritoneal macrophages (PM) (0 x 105 to 4 x 105 cells/well) were cultured with nylon wool-purified splenic T cells from BCG-vaccinated guinea pigs in the presence of purified protein derivative (PPD; 12.5 µg/ml) or concanavalin A (ConA; 5 µg/ml), and the proliferation was measured by [3H]thymidine incorporation after 96 h. PPD-induced proliferation was significantly increased as the number of PM was increased in the cocultures (Fig. 1A). This was consistent with earlier findings, which demonstrated that guinea pig PM induced T-cell proliferation (21, 22). ConA-induced T-cell proliferation reached a peak in the cocultures having four times fewer PM than T cells, while a higher number of PM (T-cell/PM ratio of 1:2) significantly inhibited proliferation of T cells to ConA (Fig. 1B), an effect which was not seen in antigen-induced cocultures. This suggests that there might be differences between the contributions of accessory cells to the proliferative responses to a polyclonal mitogen (ConA) and to a specific antigen (PPD) following engagement between T cells and macrophages (20). Adherence-purified PM (0 x 105 to 4 x 105 cells/well) were infected with live M. tuberculosis H37Rv at a multiplicity of infection (MOI) of 1:10 and cultured with 2 x 105 splenic immune T cells/well in the presence or absence of anti-rgpTNF-{alpha} antibody (1:1,000). The proliferation of T cells in the presence of infected PM peaked in cultures having the two highest ratios of PM with patterns very similar to that seen in PPD-induced proliferation, which indicates that the infected PM in our cocultures were capable of processing and presenting mycobacterial antigens to immune T cells and triggering T-cell proliferation in a PM dose-dependent fashion (Fig. 2 and 1A).



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  		FIG. 1. Effect of guinea pig PM on the proliferation of splenic immune T cells to PPD (A) and ConA (B). Different numbers of adherence-purified PM (0 x 105 to 4 x 105 cells/well) were cocultured with the same number of splenic T cells (2 x 105 cells/well) from BCG-vaccinated guinea pigs in the presence of PPD (12.5 µg/ml) or ConA (5 µg/ml). Proliferative responses are expressed as a stimulation index, which is counts per minute of stimulated cells divided by counts per minute of unstimulated cells. Results are displayed as the means ± standard errors of the means of four or five animals per group. Differences between stimulation indices from different numbers of PM in cocultures were tested for statistical significance by analysis of variance followed by Duncan's post hoc analysis (P < 0.05 [*]).

 


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  		FIG. 2. Effect of neutralizing endogenous TNF-{alpha} on the proliferation of splenic immune T cells induced by guinea pig PM infected with virulent M. tuberculosis H37Rv. Different numbers of PM (0 x 105 to 4 x 105 cells/well) were infected with a live virulent (H37Rv) strain of M. tuberculosis at an MOI of 1:10 and cocultured with the same number of splenic immune T cells (2 x 105 cells/well) in the presence or absence of anti-rgpTNF-{alpha} antibody (1:1,000). Proliferative responses are expressed as a stimulation index, which is counts per minute of stimulated cells divided by counts per minute of unstimulated cells. Results are displayed as the means ± standard errors of the means of four or five animals per group. Differences between anti-rgpTNF-{alpha}-treated and untreated cultures were tested for statistical significance by analysis of variance followed by Duncan's post hoc analysis (P < 0.05 [*]).

 
The early production of TNF-{alpha} contributes not only to the activation of innate immunity but also to the transition to antigen-specific adaptive immunity (24). Therefore, we examined the effect of removing endogenous TNF-{alpha} in our coculture system using anti-rgpTNF-{alpha} antibody. We hypothesized that blocking endogenous TNF-{alpha} activity in T-cell-macrophage cocultures would inhibit the antigen-specific activation of T cells and suppress both the proinflammatory and antimicrobial functions of infected macrophages. Anti-rgpTNF-{alpha} antibody significantly suppressed antigen-induced immune T-cell proliferation in cocultures with macrophages infected with virulent mycobacteria (Fig. 2). To investigate the mechanism by which anti-rgpTNF-{alpha} antibody suppressed T-cell proliferation, one of the coculture conditions displaying a significant effect of anti-rgpTNF-{alpha} antibody was selected to examine the mRNA expression of TNF-{alpha}, IL-12 p40, and IFN-{gamma}. PM (2 x 105 cells/well) infected with M. tuberculosis H37Rv (MOI of 1:10) were cocultured with splenic immune T cells (2 x 105 cells/well), and anti-rgpTNF-{alpha} antibody (1:1,000) was added. At 6 and 24 h after infection, total RNA was collected, and real-time PCR was performed to measure cytokine mRNA levels using primer sequences and methods reported previously (1, 7). The levels of TNF-{alpha} mRNA (Fig. 3A) increased with time in anti-rgpTNF-{alpha} antibody-treated and untreated cultures, with the mRNA level in anti-rgpTNF-{alpha} antibody-treated cultures increasing significantly compared to untreated cultures at 24 h. IL-12 p40 (Fig. 3B) and IFN-{gamma} (Fig. 3C) mRNA levels increased significantly at 24 h, and anti-rgpTNF-{alpha} antibody treatment significantly suppressed both cytokine mRNA levels at that same interval, which suggests that type 1 cytokine down-regulation is accompanied by suppression of T-cell proliferation in our coculture system. Other studies have demonstrated that neutralizing TNF-{alpha} has an inhibitory effect on the expression of Th1 cytokines. IL-12 production from BCG-infected murine bone marrow-derived macrophages was blocked by anti-TNF-{alpha} antiserum (9). Anti-TNF-{alpha} monoclonal antibody partially attenuated IFN-{gamma} synthesis in the livers of IL-12 p40 and IL-18 double-knockout mice infected with M. tuberculosis (14). In another study, neutralization of TNF-{alpha} resulted in down-regulation of IL-12 and IFN-{gamma} production in mice infected with Cryptococcus neoformans (13). The authors suggested that TNF-{alpha} production is essential for the induction of IL-12 and IFN-{gamma} and that early neutralization of TNF-{alpha} may result in a shift in the Th1/Th2 balance toward the Th2 pole in antifungal immunity. Surprisingly, in our studies, the expression of TNF-{alpha} mRNA was increased in anti-rgpTNF-{alpha}-treated cocultures (Fig. 3A). This may be due to a compensatory mechanism in which the absence of TNF-{alpha} triggered the synthesis of the protein following complete neutralization of endogenous TNF-{alpha} in our cocultures. Michishita et al. reported that neutralization of endogenous TNF-{alpha} induced an enhancement of TNF-{alpha} mRNA in myeloid leukemic cells from mice (19). We suggest that rapid removal of TNF-{alpha} by anti-TNF-{alpha} may result in lack of binding between TNF-{alpha} and TNF receptor, which leads to the positive feedback effect in TNF-{alpha} mRNA expression. In another study, higher levels of TNF-{alpha} in IL-1 knockout mice were suggested as the defense mechanism against Klebsiella pneumoniae pneumonia due to the similar biological activities of TNF-{alpha} and IL-1 (25). Therefore, it is possible that anti-TNF-{alpha} increases IL-1 production which, in turn, stimulates up-regulation of TNF-{alpha} mRNA message in our macrophage-T-cell coculture.



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  		FIG. 3. Effect of neutralizing endogenous TNF-{alpha} on expression of TNF-{alpha}, IL-12 p40, and IFN-{gamma} mRNA levels in cocultures following infection with virulent M. tuberculosis H37Rv. Levels of TNF-{alpha} (A), IL-12 p40 (B), and IFN-{gamma} (C) mRNA were quantified in guinea pig splenic immune T-cell and peritoneal macrophage cocultures at 6 and 24 h after infection with a live virulent (H37Rv) strain of M. tuberculosis at an MOI of 1:10 in the presence or absence of anti-rgpTNF-{alpha} antibody (1:1,000). Fold induction was determined from the threshold cycle values normalized for hypoxanthine phosphoribosyltransferase expression and then normalized to the values derived from unstimulated cultures. Results are displayed as the means ± standard errors of the means of four or five animals. Differences between anti-rgpTNF-{alpha}-treated and untreated cultures were tested for statistical significance by analysis of variance followed by Duncan's post hoc analysis (P < 0.05 [*]).

 
Recently, we reported that anti-rgpTNF-{alpha} increased intracellular M. tuberculosis growth in guinea pig alveolar and peritoneal macrophages (7). Therefore, we examined whether the growth of mycobacteria was controlled in cocultures of immune T cells and PM from BCG-vaccinated animals and what effect neutralizing endogenous TNF-{alpha} had on intracellular mycobacterial accumulation. PM were infected with live M. tuberculosis H37Ra or H37Rv (MOI of 1:1 or 1:10) for 3 h, extracellular mycobacteria were washed off, and infected macrophages were cultured with splenic immune T cells for 4 days in the presence or absence of anti-rgpTNF-{alpha} antibody (1:1,000). The antibody was added every other day to neutralize endogenous bioactive TNF-{alpha} throughout the culture period. Viable mycobacteria were measured on days 1 and 4 using [3H]uracil incorporation, which is a reliable correlate of CFU (3). Our cocultures from BCG-vaccinated animals exerted an inhibitory effect on the viability of attenuated M. tuberculosis H37Ra (Fig. 4A and B). At an MOI of 1:10, there was no effect of anti-rgpTNF-{alpha} treatment, as counts per minute from both anti-rgpTNF-{alpha}-treated and untreated cultures remained low (Fig. 4A). On the other hand, neutralizing TNF-{alpha} did enhance significantly the viability of attenuated mycobacteria after 4 days of infection with a 10-fold-higher MOI (1:1) (Fig. 4B). The antimycobacterial effect provided by immune cocultures appeared to be sufficient to control the viability of attenuated mycobacteria even in the absence of bioactive TNF-{alpha}, as viability was still reduced in anti-rgpTNF-{alpha}-treated cultures at day 4. When guinea pig PM were infected with the virulent H37Rv strain of M. tuberculosis at an MOI of 1:10, the bacteria grew steadily in the cultures over 4 days, which implies that virulent mycobacteria are more resistant to the antimycobacterial effects of immune T cells from BCG-vaccinated animals. Nonetheless, at day 4, treatment of the cocultures with anti-rgpTNF-{alpha} enhanced significantly the viability of virulent mycobacteria compared to that in untreated cultures (Fig. 4C). The same enhancing effect on mycobacterial accumulation following neutralization of endogenous TNF-{alpha} was seen at day 4 in PM infected at a 10-fold-higher MOI (1:1) (Fig. 4D). There has been some controversy about whether TNF-{alpha} inhibits the growth of attenuated or virulent mycobacteria. Engele et al. (8) demonstrated that TNF-{alpha} inhibits the growth of attenuated M. tuberculosis but supports the growth of virulent M. tuberculosis in human macrophages. However, we found that the growth of both attenuated and virulent mycobacteria was significantly increased by anti-rgpTNF-{alpha} antibody in guinea pig macrophages from nonvaccinated guinea pigs (7). Therefore, we wanted to address the effect of neutralizing endogenous TNF-{alpha} on the growth of both attenuated and virulent mycobacteria in the guinea pig macrophage-T-cell coculture. Our results show that TNF-{alpha} plays a critical role in controlling the growth of M. tuberculosis in cocultures of guinea pig splenic T cells and peritoneal macrophages from BCG-vaccinated animals, which may be mediated by down-regulation of IFN-{gamma} and IL-12 from T cells.



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  		FIG. 4. Effect of neutralizing endogenous TNF-{alpha} on the growth of mycobacteria in cocultures of T cells and macrophages from BCG-vaccinated guinea pigs. Resident peritoneal macrophages were infected with live attenuated (H37Ra) (A and B) or virulent (H37Rv) (C and D) strains of M. tuberculosis at an MOI of 1:10 (A and C) or 1:1 (B and D). After 3 h, extracellular mycobacteria were washed away and autologous splenic immune T cells were added. The cocultures were incubated with or without anti-rgpTNF-{alpha} antibody until day 4. The counts per minute (cpm) of tritiated uracil taken up by mycobacteria in cultures were measured. Results are expressed as the means ± standard errors of the means of results from five experiments. Differences between the counts per minute from anti-rgpTNF-{alpha}-treated and untreated cultures were compared by Student's t test (P < 0.05 [*]).

 
In conclusion, we report the development of a novel in vitro system to investigate the role of TNF-{alpha} in cocultures of splenic immune T cells and M. tuberculosis-infected peritoneal macrophages from BCG-vaccinated guinea pigs. This study provides evidence that TNF-{alpha} plays an important role in T-cell activation by contributing to the antigen-induced proliferation of T cells and expression of type 1 cytokines IL-12 and IFN-{gamma}. In addition, the enhanced intracellular growth of both attenuated and virulent strains of M. tuberculosis in guinea pig PM-T-cell cocultures following neutralization of TNF-{alpha} suggests a critical role for TNF-{alpha} in the adaptive immune response to M. tuberculosis infection in the guinea pig model.


   ACKNOWLEDGMENTS
 
This work was supported by National Institutes of Health grant RO1 AI 15495 to D.N.M.


   FOOTNOTES
 
* Corresponding author. Mailing address: Department of Microbial and Molecular Pathogenesis, The Texas A&M University System Health Science Center, 407 Reynolds Medical Building, College Station, TX 77843-1114. Phone: (979) 845-3679. Fax: (979) 845-3479. E-mail: HScho{at}medicine.tamu.edu. Back

Editor: J. L. Flynn


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Infection and Immunity, December 2005, p. 8437-8441, Vol. 73, No. 12
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.12.8437-8441.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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