Regulatory, pro-inflammatory and inhibitory human T-cell responses to M. bovis BCG : opposing T-cell forces in TB-vaccination

Abstract

There is no effective vaccine against tuberculosis (TB). The only available TB-vaccine, M. bovis BCG, induces only limited, and highly variable protection. TB-vaccine efficacy would have to include protection against active pulmonary TB, since this is the transmissible form of the disease, in the adult population; an effective vaccine would have an enormous impact on the TB-epidemic. This thesis has aimed to characterize the M. bovis BCG-reactive human T-cell response, in order to identify cellular responses that may account for the variable and poorly understood protective efficacy of BCG-vaccination. The studies presented in this thesis describe three BCG-induced cellular immune responses in adults: (i) the induction of CD8+ regulatory T-cells (Tregs), that suppress immunity partly via the ectoenzyme CD39, (ii) a dichotomous pro-inflammatory response, consisting of either induction of polyfunctional CD4+ T-cells in vaccinees with high skin inflammation of the vaccine lesion, or virtually no induction of cytokines with concomitant induction of CD8+ Tregs in vaccinees with low skin inflammation, and (iii) induction of inhibitory KLRG1+ CD8+ T-cells. This network of inter-related and partly opposing regulatory, pro-inflammatory and inhibitory immune responses may impact vaccine-induced protective immunity against TB and this could assist in guiding future TB-vaccine design.