Abstract
BackgroundThe Mycobacterium bovis Bacille Calmette-Guérin (BCG) vaccine is given to >120 million infants each year worldwide. Most studies investigating the immune response to BCG have focused on adaptive immunity. However the importance of TCR-gamma/delta (γδ) T cells and NK cells in the mycobacterial-specific immune response is of increasing interest.MethodsParticipants in four age-groups were BCG-immunized. Ten weeks later, in vitro BCG-stimulated blood was analyzed for NK and T cell markers, and intracellular IFNgamma (IFNγ) by flow cytometry. Total functional IFNγ response was calculated using integrated median fluorescence intensity (iMFI).ResultsIn infants and children, CD4 and CD4-CD8- (double-negative (DN)) T cells were the main IFNγ-expressing cells representing 43-56% and 27-37% of total CD3+ IFNγ+ T cells respectively. The iMFI was higher in DN T cells compared to CD4 T cells in all age groups, with the greatest differences seen in infants immunized at birth (p=0.002) or 2 months of age (p<0.0001). When NK cells were included in the analysis, they accounted for the majority of total IFNγ-expressing cells and, together with DN Vδ2 γδ T cells, had the highest iMFI in infants immunized at birth or 2 months of age.ConclusionIn addition to CD4 T cells, NK cells and DN T cells, including Vδ2 γδ T cells, are the key populations producing IFNγ in response to BCG immunization in infants and children. This suggests that innate immunity and unconventional T cells play a greater role in the mycobacterial immune response than previously recognized and should be considered in the design and assessment of novel tuberculosis vaccines.
Highlights
The Mycobacterium bovis Bacille Calmette-Guérin (BCG) vaccine is given to more than 120 million children worldwide each year and remains a key intervention in the prevention of tuberculosis (TB) [1]
Our study is the first to investigate in detail the importance of NK cells, γδ T cells and double negative (DN) T cells in the mycobacterialspecific IFNγ response following BCG immunization in infants
We found that the key populations producing IFNγ in response to BCG in infants and children were NK cells and DN T cells, including Vδ2 γδ T cells, rather than CD4 T cells
Summary
The Mycobacterium bovis Bacille Calmette-Guérin (BCG) vaccine is given to more than 120 million children worldwide each year and remains a key intervention in the prevention of tuberculosis (TB) [1]. In infants it provides approximately 80% protection against severe forms of TB [2]. T cells with a gamma-delta (γδ) TCR and NK cells play a key role in innate immunity These cells increase in frequency during foetal development and represent major cell subsets in cord blood [10,11,12]. In this study we used samples from the same studies to investigate the role of CD4-CD8- double negative (DN) T cells, Vδ2 γδ T cells and NK cells in the mycobacterial-specific IFNgamma (IFNγ) response after BCG immunization
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