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Involvement of IL ‐ 17A ‐ producing TCR γ δ T cells in late protective immunity against pulmonary Mycobacterium tuberculosis infection

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Interleukin (IL)‐17A is a cytokine originally reported to induce neutrophil‐mediated inflammation and anti‐microbial activity. The CD4+ T cells, which produce IL‐17A, have been well characterized as Th17 cells. On the other hand, IL‐17A‐producing TCR γδ+ T cells have been reported to participate in the immune response at an early stage of infection with Listeria monocytogenes and Mycobacterium bovis in mice. However, the involvement of IL‐17A in protective immunity was not clearly demonstrated in the chronic stage of M. tuberculosis‐infected mice.

Methods: We analyzed role of IL‐17A in host defense against chronically infected M. tuberculosis using IL‐17A KO mice.

Results: We found that TCR γδ+ T cells are a primary source of IL‐17A, but that mycobacterial antigen‐specific Th17 cells were hardly detected even at the chronic stage of M. tuberculosis infection. IL‐17A‐deficient mice showed a decreased survival rate, and increased bacterial burden in the lungs after the infection when compared to the wild‐type mice. Furthermore, a histological analysis showed an impaired granuloma formation in the infected lungs of IL‐17A‐deficient mice, which was considered to be due to a decrease of IFN‐γ and TNF at the chronic stage.

Conclusion: Our data suggest that the IL‐17A‐producing TCR γδ+ T cells, rather than the Th17 cells, in the infected lungs are an indispensable source of protective immunity against M. tuberculosis infection.

No MeSH data available.


Related in: MedlinePlus

BCG vaccination did not induce Th17 cells in the lungs after M. tuberculosis challenge. Wild‐type C57BL/6 mice were vaccinated with M. bovis BCG 30 or 60 days before M. tuberculosis H37Rv infection. The PIF cells (5 × 105 cells) were prepared on the 4th week after the M. tuberculosis infection, and were cultured with PPD (5 μg/ml) in the presence of naive spleen antigen presenting cells (1 × 105 cells) for 18 h at 37°C, and with GolgiPlug for the last 6 h. After the culture, the cells were surface stained with FITC‐CD3 and APC‐conjugated anti‐CD4. Surface‐stained cells were subjected to intercellular cytokine staining with a PE‐conjugated anti‐IL‐17A mAb. The samples were analyzed by FCM.
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iid3121-fig-0005: BCG vaccination did not induce Th17 cells in the lungs after M. tuberculosis challenge. Wild‐type C57BL/6 mice were vaccinated with M. bovis BCG 30 or 60 days before M. tuberculosis H37Rv infection. The PIF cells (5 × 105 cells) were prepared on the 4th week after the M. tuberculosis infection, and were cultured with PPD (5 μg/ml) in the presence of naive spleen antigen presenting cells (1 × 105 cells) for 18 h at 37°C, and with GolgiPlug for the last 6 h. After the culture, the cells were surface stained with FITC‐CD3 and APC‐conjugated anti‐CD4. Surface‐stained cells were subjected to intercellular cytokine staining with a PE‐conjugated anti‐IL‐17A mAb. The samples were analyzed by FCM.

Mentions: M. bovis BCG is a strong inducer of Th1 immune responses, and vaccination with M. bovis BCG suppresses the development of tuberculosis. It has been demonstrated that IL‐17A is required for the generation of Th1 cell responses and host immunity against various pathogens 10, 12, 13. In previous studies, we have shown that IL‐17A was hardly detected from TCR αβ+ T cells in the lungs of wild‐type C57BL/6 mice after i.t. M. bovis BCG infection at a relatively early stage 9, 10. Th17 cells have protective effects against M. tuberculosis infection in vaccinated mice 14, 15. Therefore, we examined whether vaccination with M. bovis BCG induces Th17‐cell responses in M. tuberculosis infected lungs. CD4+ IL‐17A+ Th17 cells were not induced by M. bovis BCG vaccination before M. tuberculosis infection (Fig. 5). On the other hand, a higher ratio of CD3+ CD4− T cells present in the lungs of BCG immunized wild‐type C57BL/6 mice produced IL‐17A compared to non‐immunized mice. The IL‐17A+ CD3+ CD4− cells were TCR γδ+ T cells. Therefore, in the case of M. bovis BCG vaccination, the IL‐17A‐producing cells were TCR γδ+ T cells, not Th17 cells.


Involvement of IL ‐ 17A ‐ producing TCR γ δ T cells in late protective immunity against pulmonary Mycobacterium tuberculosis infection
BCG vaccination did not induce Th17 cells in the lungs after M. tuberculosis challenge. Wild‐type C57BL/6 mice were vaccinated with M. bovis BCG 30 or 60 days before M. tuberculosis H37Rv infection. The PIF cells (5 × 105 cells) were prepared on the 4th week after the M. tuberculosis infection, and were cultured with PPD (5 μg/ml) in the presence of naive spleen antigen presenting cells (1 × 105 cells) for 18 h at 37°C, and with GolgiPlug for the last 6 h. After the culture, the cells were surface stained with FITC‐CD3 and APC‐conjugated anti‐CD4. Surface‐stained cells were subjected to intercellular cytokine staining with a PE‐conjugated anti‐IL‐17A mAb. The samples were analyzed by FCM.
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iid3121-fig-0005: BCG vaccination did not induce Th17 cells in the lungs after M. tuberculosis challenge. Wild‐type C57BL/6 mice were vaccinated with M. bovis BCG 30 or 60 days before M. tuberculosis H37Rv infection. The PIF cells (5 × 105 cells) were prepared on the 4th week after the M. tuberculosis infection, and were cultured with PPD (5 μg/ml) in the presence of naive spleen antigen presenting cells (1 × 105 cells) for 18 h at 37°C, and with GolgiPlug for the last 6 h. After the culture, the cells were surface stained with FITC‐CD3 and APC‐conjugated anti‐CD4. Surface‐stained cells were subjected to intercellular cytokine staining with a PE‐conjugated anti‐IL‐17A mAb. The samples were analyzed by FCM.
Mentions: M. bovis BCG is a strong inducer of Th1 immune responses, and vaccination with M. bovis BCG suppresses the development of tuberculosis. It has been demonstrated that IL‐17A is required for the generation of Th1 cell responses and host immunity against various pathogens 10, 12, 13. In previous studies, we have shown that IL‐17A was hardly detected from TCR αβ+ T cells in the lungs of wild‐type C57BL/6 mice after i.t. M. bovis BCG infection at a relatively early stage 9, 10. Th17 cells have protective effects against M. tuberculosis infection in vaccinated mice 14, 15. Therefore, we examined whether vaccination with M. bovis BCG induces Th17‐cell responses in M. tuberculosis infected lungs. CD4+ IL‐17A+ Th17 cells were not induced by M. bovis BCG vaccination before M. tuberculosis infection (Fig. 5). On the other hand, a higher ratio of CD3+ CD4− T cells present in the lungs of BCG immunized wild‐type C57BL/6 mice produced IL‐17A compared to non‐immunized mice. The IL‐17A+ CD3+ CD4− cells were TCR γδ+ T cells. Therefore, in the case of M. bovis BCG vaccination, the IL‐17A‐producing cells were TCR γδ+ T cells, not Th17 cells.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Interleukin (IL)‐17A is a cytokine originally reported to induce neutrophil‐mediated inflammation and anti‐microbial activity. The CD4+ T cells, which produce IL‐17A, have been well characterized as Th17 cells. On the other hand, IL‐17A‐producing TCR γδ+ T cells have been reported to participate in the immune response at an early stage of infection with Listeria monocytogenes and Mycobacterium bovis in mice. However, the involvement of IL‐17A in protective immunity was not clearly demonstrated in the chronic stage of M. tuberculosis‐infected mice.

Methods: We analyzed role of IL‐17A in host defense against chronically infected M. tuberculosis using IL‐17A KO mice.

Results: We found that TCR γδ+ T cells are a primary source of IL‐17A, but that mycobacterial antigen‐specific Th17 cells were hardly detected even at the chronic stage of M. tuberculosis infection. IL‐17A‐deficient mice showed a decreased survival rate, and increased bacterial burden in the lungs after the infection when compared to the wild‐type mice. Furthermore, a histological analysis showed an impaired granuloma formation in the infected lungs of IL‐17A‐deficient mice, which was considered to be due to a decrease of IFN‐γ and TNF at the chronic stage.

Conclusion: Our data suggest that the IL‐17A‐producing TCR γδ+ T cells, rather than the Th17 cells, in the infected lungs are an indispensable source of protective immunity against M. tuberculosis infection.

No MeSH data available.


Related in: MedlinePlus