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Mucosal BCG Vaccination Induces Protective Lung-Resident Memory T Cell Populations against Tuberculosis

View Article: PubMed Central - PubMed

ABSTRACT

Mycobacterium bovis Bacille Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB), yet its moderate efficacy against pulmonary TB calls for improved vaccination strategies. Mucosal BCG vaccination generates superior protection against TB in animal models; however, the mechanisms of protection remain elusive. Tissue-resident memory T (TRM) cells have been implicated in protective immune responses against viral infections, but the role of TRM cells following mycobacterial infection is unknown. Using a mouse model of TB, we compared protection and lung cellular infiltrates of parenteral and mucosal BCG vaccination. Adoptive transfer and gene expression analyses of lung airway cells were performed to determine the protective capacities and phenotypes of different memory T cell subsets. In comparison to subcutaneous vaccination, intratracheal and intranasal BCG vaccination generated T effector memory and TRM cells in the lung, as defined by surface marker phenotype. Adoptive mucosal transfer of these airway-resident memory T cells into naive mice mediated protection against TB. Whereas airway-resident memory CD4+ T cells displayed a mixture of effector and regulatory phenotype, airway-resident memory CD8+ T cells displayed prototypical TRM features. Our data demonstrate a key role for mucosal vaccination-induced airway-resident T cells in the host defense against pulmonary TB. These results have direct implications for the design of refined vaccination strategies.

No MeSH data available.


Related in: MedlinePlus

Mucosal BCG vaccination confers improved protection against M. tuberculosis infection. (A) B6 mice were BCG vaccinated either i.t. or s.c. Sixty days later, vaccinated and control groups were aerosol infected with a low dose of virulent M. tuberculosis and the CFU counts in their lungs were determined at the time points indicated. (B, C) Individual log10 CFU counts per lung (48) at day 45 p.i. (B) and mean log10 CFU counts per lung from two pooled independent experiments ± the standard error of the mean at the time points indicated (n = 8 mice per group) (C). The statistical significance of differences between the s.c. and i.t. BCG vaccination routes is shown. ****, P ≤ 0.0001; **, P ≤ 0.01; *, P ≤ 0.05; n.d., not done (analysis of variance with Tukey’s posttest for significance).
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fig1: Mucosal BCG vaccination confers improved protection against M. tuberculosis infection. (A) B6 mice were BCG vaccinated either i.t. or s.c. Sixty days later, vaccinated and control groups were aerosol infected with a low dose of virulent M. tuberculosis and the CFU counts in their lungs were determined at the time points indicated. (B, C) Individual log10 CFU counts per lung (48) at day 45 p.i. (B) and mean log10 CFU counts per lung from two pooled independent experiments ± the standard error of the mean at the time points indicated (n = 8 mice per group) (C). The statistical significance of differences between the s.c. and i.t. BCG vaccination routes is shown. ****, P ≤ 0.0001; **, P ≤ 0.01; *, P ≤ 0.05; n.d., not done (analysis of variance with Tukey’s posttest for significance).

Mentions: To investigate the role of lung-resident T cells in immune protection against TB following BCG vaccination, we compared local (mucosal) BCG vaccination via the intratracheal (i.t.) route to parenteral vaccination by s.c. administration of BCG. Sixty days after vaccination, mice were challenged aerogenically with M. tuberculosis and the bacterial loads in their lungs were determined at various time points postinfection (p.i.) (Fig. 1A). Confirming recent studies (19, 20), we found that mucosal BCG vaccination confers better protection against M. tuberculosis infection than parenteral s.c. BCG vaccination for at least 100 days (Fig. 1B and C).


Mucosal BCG Vaccination Induces Protective Lung-Resident Memory T Cell Populations against Tuberculosis
Mucosal BCG vaccination confers improved protection against M. tuberculosis infection. (A) B6 mice were BCG vaccinated either i.t. or s.c. Sixty days later, vaccinated and control groups were aerosol infected with a low dose of virulent M. tuberculosis and the CFU counts in their lungs were determined at the time points indicated. (B, C) Individual log10 CFU counts per lung (48) at day 45 p.i. (B) and mean log10 CFU counts per lung from two pooled independent experiments ± the standard error of the mean at the time points indicated (n = 8 mice per group) (C). The statistical significance of differences between the s.c. and i.t. BCG vaccination routes is shown. ****, P ≤ 0.0001; **, P ≤ 0.01; *, P ≤ 0.05; n.d., not done (analysis of variance with Tukey’s posttest for significance).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5120139&req=5

fig1: Mucosal BCG vaccination confers improved protection against M. tuberculosis infection. (A) B6 mice were BCG vaccinated either i.t. or s.c. Sixty days later, vaccinated and control groups were aerosol infected with a low dose of virulent M. tuberculosis and the CFU counts in their lungs were determined at the time points indicated. (B, C) Individual log10 CFU counts per lung (48) at day 45 p.i. (B) and mean log10 CFU counts per lung from two pooled independent experiments ± the standard error of the mean at the time points indicated (n = 8 mice per group) (C). The statistical significance of differences between the s.c. and i.t. BCG vaccination routes is shown. ****, P ≤ 0.0001; **, P ≤ 0.01; *, P ≤ 0.05; n.d., not done (analysis of variance with Tukey’s posttest for significance).
Mentions: To investigate the role of lung-resident T cells in immune protection against TB following BCG vaccination, we compared local (mucosal) BCG vaccination via the intratracheal (i.t.) route to parenteral vaccination by s.c. administration of BCG. Sixty days after vaccination, mice were challenged aerogenically with M. tuberculosis and the bacterial loads in their lungs were determined at various time points postinfection (p.i.) (Fig. 1A). Confirming recent studies (19, 20), we found that mucosal BCG vaccination confers better protection against M. tuberculosis infection than parenteral s.c. BCG vaccination for at least 100 days (Fig. 1B and C).

View Article: PubMed Central - PubMed

ABSTRACT

Mycobacterium bovis Bacille Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB), yet its moderate efficacy against pulmonary TB calls for improved vaccination strategies. Mucosal BCG vaccination generates superior protection against TB in animal models; however, the mechanisms of protection remain elusive. Tissue-resident memory T (TRM) cells have been implicated in protective immune responses against viral infections, but the role of TRM cells following mycobacterial infection is unknown. Using a mouse model of TB, we compared protection and lung cellular infiltrates of parenteral and mucosal BCG vaccination. Adoptive transfer and gene expression analyses of lung airway cells were performed to determine the protective capacities and phenotypes of different memory T cell subsets. In comparison to subcutaneous vaccination, intratracheal and intranasal BCG vaccination generated T effector memory and TRM cells in the lung, as defined by surface marker phenotype. Adoptive mucosal transfer of these airway-resident memory T cells into naive mice mediated protection against TB. Whereas airway-resident memory CD4+ T cells displayed a mixture of effector and regulatory phenotype, airway-resident memory CD8+ T cells displayed prototypical TRM features. Our data demonstrate a key role for mucosal vaccination-induced airway-resident T cells in the host defense against pulmonary TB. These results have direct implications for the design of refined vaccination strategies.

No MeSH data available.


Related in: MedlinePlus