Mycobacterium bovis BCG vaccination induces divergent proinflammatory or regulatory T cell responses in adults

MC Boer, C Prins, KE van Meijgaarden… - Clinical and Vaccine …, 2015 - Am Soc Microbiol
MC Boer, C Prins, KE van Meijgaarden, JT van Dissel, THM Ottenhoff, SA Joosten
Clinical and Vaccine Immunology, 2015Am Soc Microbiol
ABSTRACT Mycobacterium bovis bacillus Calmette-Guérin (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 versus unprotected cohorts have yielded inconsistent results. We studied the
primary T cell response, both proinflammatory and regulatory T cell responses, induced by
BCG vaccination in adults. Twelve healthy adult volunteers who were tuberculin skin test …
Abstract
Mycobacterium bovis bacillus Calmette-Guérin (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 versus unprotected cohorts have yielded inconsistent results. We studied the primary T cell response, both proinflammatory 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 naive 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 gamma interferon-positive (IFN-γ+) interleukin 2-positive (IL-2+) tumor necrosis factor α-positive (TNF-α+) polyfunctional CD4+ T cells concurrent with CD4+ IL-17A+ and CD8+ IFN-γ+ T cells or, in contrast, virtually absent cytokine responses with induction of CD8+ regulatory T cells. Significant induction of polyfunctional CD4+ IFN-γ+ IL-2+ TNF-α+ T cells and IFN-γ production by peripheral blood mononuclear cells (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 proinflammatory 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 nonclassical immune markers will enhance our understanding of the mechanisms and determinants that underlie the induction of apparently opposite immune responses and how these impact the ability of BCG to induce protective immunity to TB.
American Society for Microbiology