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Suboptimal activation of antigen-specific CD4+ effector cells enables persistence of M. tuberculosis in vivo.

Bold TD, Banaei N, Wolf AJ, Ernst JD - PLoS Pathog. (2011)

Bottom Line: Bacterial downregulation of fbpB (encoding Ag85B) contributed to the decrease in effector T cell activation in the lungs, as a strain of M. tuberculosis engineered to express fbpB in the chronic phase stimulated P25TCRTh1 effector cells at higher frequencies in vivo, and this resulted in CD4+ T cell-dependent reduction of lung bacterial burdens and prolonged survival of mice.Administration of synthetic peptide 25 alone also increased activation of endogenous antigen-specific effector cells and reduced the bacterial burden in the lungs without apparent host toxicity.These results indicate that CD4+ effector T cells are activated at suboptimal frequencies in tuberculosis, and that increasing effector T cell activation in the lungs by providing one or more epitope peptides may be a successful strategy for TB therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, New York University School of Medicine, New York City, New York, United States of America.

ABSTRACT
Adaptive immunity to Mycobacterium tuberculosis controls progressive bacterial growth and disease but does not eradicate infection. Among CD4+ T cells in the lungs of M. tuberculosis-infected mice, we observed that few produced IFN-γ without ex vivo restimulation. Therefore, we hypothesized that one mechanism whereby M. tuberculosis avoids elimination is by limiting activation of CD4+ effector T cells at the site of infection in the lungs. To test this hypothesis, we adoptively transferred Th1-polarized CD4+ effector T cells specific for M. tuberculosis Ag85B peptide 25 (P25TCRTh1 cells), which trafficked to the lungs of infected mice and exhibited antigen-dependent IFN-γ production. During the early phase of infection, ∼10% of P25TCRTh1 cells produced IFN-γ in vivo; this declined to <1% as infection progressed to chronic phase. Bacterial downregulation of fbpB (encoding Ag85B) contributed to the decrease in effector T cell activation in the lungs, as a strain of M. tuberculosis engineered to express fbpB in the chronic phase stimulated P25TCRTh1 effector cells at higher frequencies in vivo, and this resulted in CD4+ T cell-dependent reduction of lung bacterial burdens and prolonged survival of mice. Administration of synthetic peptide 25 alone also increased activation of endogenous antigen-specific effector cells and reduced the bacterial burden in the lungs without apparent host toxicity. These results indicate that CD4+ effector T cells are activated at suboptimal frequencies in tuberculosis, and that increasing effector T cell activation in the lungs by providing one or more epitope peptides may be a successful strategy for TB therapy.

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Schematic diagram of CD4+ effector T cell activation at                        the site of M. tuberculosis infection.A. During the chronic stage of infection, Ag85B-specific                            CD4+ effector cells are activated at low frequencies, at                        least part due to low bacterial expression of the antigen gene; bacteria are                        able to persist due to the low frequency of effector cell activation.                            B. Administration of epitope peptide occupies                        previously-empty MHC class II and/or displaces previously-bound peptides and                        provides antigen for recognition by pre-existing epitope-specific                            CD4+ effector cells, resulting in their activation and                        consequent reduction of the lung bacterial burden.
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ppat-1002063-g007: Schematic diagram of CD4+ effector T cell activation at the site of M. tuberculosis infection.A. During the chronic stage of infection, Ag85B-specific CD4+ effector cells are activated at low frequencies, at least part due to low bacterial expression of the antigen gene; bacteria are able to persist due to the low frequency of effector cell activation. B. Administration of epitope peptide occupies previously-empty MHC class II and/or displaces previously-bound peptides and provides antigen for recognition by pre-existing epitope-specific CD4+ effector cells, resulting in their activation and consequent reduction of the lung bacterial burden.

Mentions: M. tuberculosis evades adaptive immunity to persist in the lungs, often for the lifetime of the host. Here, we have characterized one mechanism by which this impressive feat of immune evasion is accomplished in vivo. We found that, of the large number of CD4+ effector T cells recruited to the lungs of infected mice, few are stimulated to produce IFN-γ (Figure 7A). While there are few precedents available for comparison, our findings are in stark contrast to those found in C57BL/6 mice infected with the Armstrong strain of LCMV [28]. In that context, which results in CD8+ T cell-dependent resolution of infection, >20% of virus-specific CD8+ T cells are activated to produce IFN-γ during the acute stage of infection when viral burdens and antigen availability are highest, and the frequency of in vivo-activated virus-specific CD8+ T cells does not decrease until the viral burden is reduced. We found that the initially low proportion of CD4+ T cells producing IFN-γ in the lungs of M. tuberculosis-infected mice diminishes further as infection progresses to chronic phase, even though the bacterial burden in the lungs remains high. Our studies using adoptively transferred Ag85B-specific P25TCRTh1 cells revealed that the decreasing responses of CD4+ effector cells are caused in part by decreasing expression of fbpB by M. tuberculosis. By reducing fbpB expression during chronic infection, M. tuberculosis restricts the availability of Ag85B, an immunodominant antigen, and thereby prevents infected APCs from optimally activating CD4+ effector T cells. Consistent with this model, we found that a recombinant strain of M. tuberculosis engineered to maintain the expression of fbpB at high levels during chronic infection (CPE85B) was attenuated during the chronic phase of infection in a strictly CD4+ T cell dependent manner, indicating that down-regulation of fbpB and limitation of antigen availability is important for evasion of adaptive immunity by M. tuberculosis. Treatment of infected mice with synthetic Ag85B peptide 25 also increased CD4+ effector T cell IFN-γ responses and significantly reduced the bacterial burden in the lungs. We conclude that suboptimal effector T cell activation enables M. tuberculosis to evade elimination by adaptive immunity during the chronic stage of infection, and that some of this suboptimal effector T cell activation is attributable to restricted antigen expression by the bacteria. In addition, other mechanisms that limit effector T cell activation, such as interference with the MHC class II antigen processing and presentation pathway and/or the action of regulatory T cells, likely contribute to the remarkable survival of M. tuberculosis in vivo.


Suboptimal activation of antigen-specific CD4+ effector cells enables persistence of M. tuberculosis in vivo.

Bold TD, Banaei N, Wolf AJ, Ernst JD - PLoS Pathog. (2011)

Schematic diagram of CD4+ effector T cell activation at                        the site of M. tuberculosis infection.A. During the chronic stage of infection, Ag85B-specific                            CD4+ effector cells are activated at low frequencies, at                        least part due to low bacterial expression of the antigen gene; bacteria are                        able to persist due to the low frequency of effector cell activation.                            B. Administration of epitope peptide occupies                        previously-empty MHC class II and/or displaces previously-bound peptides and                        provides antigen for recognition by pre-existing epitope-specific                            CD4+ effector cells, resulting in their activation and                        consequent reduction of the lung bacterial burden.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3102708&req=5

ppat-1002063-g007: Schematic diagram of CD4+ effector T cell activation at the site of M. tuberculosis infection.A. During the chronic stage of infection, Ag85B-specific CD4+ effector cells are activated at low frequencies, at least part due to low bacterial expression of the antigen gene; bacteria are able to persist due to the low frequency of effector cell activation. B. Administration of epitope peptide occupies previously-empty MHC class II and/or displaces previously-bound peptides and provides antigen for recognition by pre-existing epitope-specific CD4+ effector cells, resulting in their activation and consequent reduction of the lung bacterial burden.
Mentions: M. tuberculosis evades adaptive immunity to persist in the lungs, often for the lifetime of the host. Here, we have characterized one mechanism by which this impressive feat of immune evasion is accomplished in vivo. We found that, of the large number of CD4+ effector T cells recruited to the lungs of infected mice, few are stimulated to produce IFN-γ (Figure 7A). While there are few precedents available for comparison, our findings are in stark contrast to those found in C57BL/6 mice infected with the Armstrong strain of LCMV [28]. In that context, which results in CD8+ T cell-dependent resolution of infection, >20% of virus-specific CD8+ T cells are activated to produce IFN-γ during the acute stage of infection when viral burdens and antigen availability are highest, and the frequency of in vivo-activated virus-specific CD8+ T cells does not decrease until the viral burden is reduced. We found that the initially low proportion of CD4+ T cells producing IFN-γ in the lungs of M. tuberculosis-infected mice diminishes further as infection progresses to chronic phase, even though the bacterial burden in the lungs remains high. Our studies using adoptively transferred Ag85B-specific P25TCRTh1 cells revealed that the decreasing responses of CD4+ effector cells are caused in part by decreasing expression of fbpB by M. tuberculosis. By reducing fbpB expression during chronic infection, M. tuberculosis restricts the availability of Ag85B, an immunodominant antigen, and thereby prevents infected APCs from optimally activating CD4+ effector T cells. Consistent with this model, we found that a recombinant strain of M. tuberculosis engineered to maintain the expression of fbpB at high levels during chronic infection (CPE85B) was attenuated during the chronic phase of infection in a strictly CD4+ T cell dependent manner, indicating that down-regulation of fbpB and limitation of antigen availability is important for evasion of adaptive immunity by M. tuberculosis. Treatment of infected mice with synthetic Ag85B peptide 25 also increased CD4+ effector T cell IFN-γ responses and significantly reduced the bacterial burden in the lungs. We conclude that suboptimal effector T cell activation enables M. tuberculosis to evade elimination by adaptive immunity during the chronic stage of infection, and that some of this suboptimal effector T cell activation is attributable to restricted antigen expression by the bacteria. In addition, other mechanisms that limit effector T cell activation, such as interference with the MHC class II antigen processing and presentation pathway and/or the action of regulatory T cells, likely contribute to the remarkable survival of M. tuberculosis in vivo.

Bottom Line: Bacterial downregulation of fbpB (encoding Ag85B) contributed to the decrease in effector T cell activation in the lungs, as a strain of M. tuberculosis engineered to express fbpB in the chronic phase stimulated P25TCRTh1 effector cells at higher frequencies in vivo, and this resulted in CD4+ T cell-dependent reduction of lung bacterial burdens and prolonged survival of mice.Administration of synthetic peptide 25 alone also increased activation of endogenous antigen-specific effector cells and reduced the bacterial burden in the lungs without apparent host toxicity.These results indicate that CD4+ effector T cells are activated at suboptimal frequencies in tuberculosis, and that increasing effector T cell activation in the lungs by providing one or more epitope peptides may be a successful strategy for TB therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, New York University School of Medicine, New York City, New York, United States of America.

ABSTRACT
Adaptive immunity to Mycobacterium tuberculosis controls progressive bacterial growth and disease but does not eradicate infection. Among CD4+ T cells in the lungs of M. tuberculosis-infected mice, we observed that few produced IFN-γ without ex vivo restimulation. Therefore, we hypothesized that one mechanism whereby M. tuberculosis avoids elimination is by limiting activation of CD4+ effector T cells at the site of infection in the lungs. To test this hypothesis, we adoptively transferred Th1-polarized CD4+ effector T cells specific for M. tuberculosis Ag85B peptide 25 (P25TCRTh1 cells), which trafficked to the lungs of infected mice and exhibited antigen-dependent IFN-γ production. During the early phase of infection, ∼10% of P25TCRTh1 cells produced IFN-γ in vivo; this declined to <1% as infection progressed to chronic phase. Bacterial downregulation of fbpB (encoding Ag85B) contributed to the decrease in effector T cell activation in the lungs, as a strain of M. tuberculosis engineered to express fbpB in the chronic phase stimulated P25TCRTh1 effector cells at higher frequencies in vivo, and this resulted in CD4+ T cell-dependent reduction of lung bacterial burdens and prolonged survival of mice. Administration of synthetic peptide 25 alone also increased activation of endogenous antigen-specific effector cells and reduced the bacterial burden in the lungs without apparent host toxicity. These results indicate that CD4+ effector T cells are activated at suboptimal frequencies in tuberculosis, and that increasing effector T cell activation in the lungs by providing one or more epitope peptides may be a successful strategy for TB therapy.

Show MeSH
Related in: MedlinePlus