BCG-vaccination induces divergent pro-inflammatory or regulatory T-cell responses in adults: Variability in adult BCG-induced T-cell responses

Abstract

Mycobacterium bovis bacillus Calmette-Guérin (M. bovis BCG), the only currently available vaccine against tuberculosis, induces variable protection in adults. Immune correlates of protection are lacking, and analyses on cytokine-producing T-cell subsets in protected vs. non-protected cohorts have yielded inconsistent results. We studied the primary T-cell response, both pro-inflammatory and regulatory T-cell responses, induced by BCG-vaccination in adults. Twelve healthy adult volunteers, who were Tuberculin skin test (TST) -negative, QuantiFERON test (QFT) -negative, and BCG-naïve, were vaccinated with BCG and followed-up prospectively. BCG-vaccination induced an unexpectedly dichotomous immune response in this small, BCG-naive young adult cohort: BCG-vaccination induced either IFNγ+IL2+TNFa+ polyfunctional CD4+ T-cells concurrent with CD4+IL17A+ and CD8+IFNγ+ T-cells, or, in contrast, virtually absent cytokine responses with induction of CD8+ regulatory T-cells. Significant induction of polyfunctional CD4+IFNγ+IL2+TNFa+ T-cells and IFNγ production by PBMCs was confined to individuals with strong immunization-induced local skin inflammation and increased serum C-reactive protein (CRP). Conversely, in individuals with mild inflammation, regulatory-like CD8+ T-cells were uniquely induced. Thus, BCG-vaccination either induced a broad pro-inflammatory T-cell response with local inflammatory reactogenicity, or in contrast a predominant CD8+ regulatory T-cell response with mild local inflammation, poor cytokine induction and absent polyfunctional CD4+ T-cells. Further detailed fine mapping of the heterogeneous host response to BCG-vaccination using classical and non-classical immune markers will enhance our understanding of the mechanisms and determinants that underlie the induction of apparently opposite immune responses, and how these impact on BCGs ability to induce protective immunity to TB.