One third of the global population is estimated to be latently infected with Mycobacterium tuberculosis (M.tb). We performed a phase 1 randomized, controlled trial of isoniazid preventive therapy (IPT) before re-vaccination with Bacille Calmette-Guerin (BCG) in healthy, tuberculin skin test positive (≥15mm induration), HIV-negative, South African adults. We hypothesised that pre-clearance of latent bacilli with IPT modulates BCG immunogenicity following re-vaccination.
Frequencies and co-expression of IFNγ, TNFα, IL-2, IL-17, and/or IL-22 in CD4, and IFNγ-expressing CD8, γδ T, CD3+CD56+ NKT-like and NK cells in response to BCG were measured using whole blood intracellular cytokine staining and flow cytometry.
We analyzed 72 participants who were BCG re-vaccinated after IPT (n=33) or without prior IPT (n=39). IPT had little effect on frequencies or cytokine co-expression patterns of M.tb- or BCG-specific responses. Re-vaccination transiently boosted BCG-specific Th1 cytokine-expressing CD4, CD8 and γδ T cells. Despite high frequencies of IFNγ-expressing BCG-reactive CD3+CD56+ NKT-like, CD3−CD56dim and CD3−CD56hi NK cells at baseline, BCG re-vaccination boosted these responses, which remained elevated up to one year after re-vaccination. Such BCG-reactive memory NK cells were induced by BCG vaccination in infants, while in vitro IFN-γ expression by NK cells upon BCG stimulation was dependent on IL-12 and IL-18.
Our data suggest that isoniazid pre-clearance of M.tb bacilli has little effect on the magnitude, persistence or functional attributes of lymphocyte responses boosted by BCG re-vaccination. Our study highlights surprising durability of BCG-boosted memory NKT-like and NK cells expressing anti-mycobacterial effector molecules, which may be novel targets for TB vaccines.
Approximately 20% of persons living in areas hyperendemic for tuberculosis (TB) display persistent lack of tuberculin skin test (TST) reactivity and appear to be naturally resistant to infection by Mycobacterium tuberculosis. Among those with a positive response, the intensity of TST reactivity varies greatly. The genetic basis of TST reactivity is not known. We report on a genome-wide linkage search for loci that have an impact on TST reactivity, which is defined either as zero versus nonzero (TST-BINa) or as extent of TST in millimeters (TST–quantitative trait locus [QTL]) in a panel of 128 families, including 350 siblings, from an area of South Africa hyperendemic for TB. We detected a major locus (TST1) on chromosomal region 11p14 (P = 1.4 × 10−5), which controls TST-BINa, with a lack of responsiveness indicating T cell–independent resistance to M. tuberculosis. We also detected a second major locus (TST2) on chromosomal region 5p15 (P < 10−5), which controls TST-QTL or the intensity of T cell–mediated delayed type hypersensitivity (DTH) to tuberculin. Fine mapping of this region identified SLC6A3, encoding the dopamine transporter DAT1, as a promising gene for further studies. Our results pave the way for the understanding of the molecular mechanisms involved in resistance to M. tuberculosis infection in endemic areas (TST1) and for the identification of critical regulators of T cell–dependent DTH to tuberculin (TST2).
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