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BCG vaccination elicits protection against M. tuberculosis infection mediated by two phases of T cell immunity
Abiola F. Ogunsola, Rocky Lai, Kelly Cavallo, Anthony V. Tran, Gillian L. Beamer, Samuel M. Behar
Abiola F. Ogunsola, Rocky Lai, Kelly Cavallo, Anthony V. Tran, Gillian L. Beamer, Samuel M. Behar
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Research Article Immunology Infectious disease Inflammation

BCG vaccination elicits protection against M. tuberculosis infection mediated by two phases of T cell immunity

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Abstract

Vaccine development for tuberculosis (TB) is a global priority. Our studies using Collaborative Cross (CC) mice show that genetic diversity influences the efficacy of BCG, the most widely used TB vaccine. BCG vaccination of CC042 mice reduced their lung bacillary burden and increased their survival following low-dose aerosol Mycobacterium tuberculosis infection (MTBI), despite impaired T cell trafficking due to a defective Itgal gene. BCG vaccination conferred early bacillary control that appeared to be independent of B cell or T cell recall responses following MTBI. In contrast, long-term survival of BCG-vaccinated CC042 mice after MTBI required T cells. Thus, CC042 mice reveal two phases of immunity induced by BCG: an early phase mediated by innate immunity or innate-like T cells and a later phase mediated by conventional memory CD4+ and/or CD8+ T cells. Although measurement of vaccine-induced protection 30 days after MTBI is a standard measure of vaccine efficacy in the TB model, this time point might be independent of memory T cells in CC042 mice. Our results suggest that vaccine-elicited innate/innate-like responses could have a larger role in protection than previously considered. The concordance between lung CFU, pathology, and survival makes CC042 mice useful for mechanistic studies on vaccine-induced immunity.

Authors

Abiola F. Ogunsola, Rocky Lai, Kelly Cavallo, Anthony V. Tran, Gillian L. Beamer, Samuel M. Behar

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Figure 4

Bacterial control in BCG-vaccinated CC042 mice challenged with Mtb is independent of CD4+ and CD8+ memory T cells.

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Bacterial control in BCG-vaccinated CC042 mice challenged with Mtb is in...
(A) Experimental scheme. CC042 mice were vaccinated or not vaccinated with BCG in the flank and rested for 9 weeks. A cohort from each vaccination group was treated with a combination of anti-CD4 and anti-CD8α mAbs for 3 weeks. Then, all mice were infected for 4 weeks with Rv.YFP. (B) Determination of CD4+ and CD8+ T cell depletion. Mice were treated with anti-CD4 and anti-CD8α mAbs after BCG vaccination as described in A. The location of the CD4+ and CD8β+ T cells was determined as described in Methods, and the populations are designated as either IV+ (intravascular) or IV– (parenchymal). Representative flow plot of CD4 and CD8β expression of CD90+ T cells in the blood at 4 wpi of representative BCG-vaccinated CC042 mice with and without T depletion. These data are from the same experiment depicted in Figure 3F. (C) Frequency of IV+ or IV– CD90+, CD4+, and CD8β+ T cells in the lung at the end of the depletion period but before MTBI of CC042 mice. (D and E) Enumeration of naive (CD44–CD62L+, D) and antigen-experienced (CD44+CD62L–, E) CD4+ (left) and CD8+ (right) T cells in the lungs of CC042 mice 4 weeks after infection. (F) BCG-elicited protection in the lung (left), mLN (middle), and spleen (right) is not affected by CD4+ and CD8+ T cell depletion. (C–F) One-way ANOVA with Šidák’s multiple-comparison test. Box-and-whisker plots indicate median (middle line), 25th and 75th percentiles (box), and minimum and maximum (whiskers). Each point represents an individual subject; n = 3–5 mice per group. The data are from 1 of 2 independent experiments with similar results.

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