Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity

Abstract

We have recently shown that BCG (Bacillus Calmette-Guérin) vaccination in healthy volunteers induces epigenetic reprogramming of monocytes, leading to increased cytokine production in response to nonrelated pathogens for up to 3 months after vaccination. This phenomenon was named 'trained immunity'. In the present study we assessed whether BCG was able to induce long-lasting effects on both trained immunity and heterologous T helper 1 (Th1) and Th17 immune responses 1 year after vaccination. The production of TNFα and IL-1β to mycobacteria or unrelated pathogens was higher after 2 weeks and 3 months postvaccination, but these effects were less pronounced 1 year after vaccination. However, monocytes recovered 1 year after vaccination had an increased expression of pattern recognition receptors such as CD14, Toll-like receptor 4 (TLR4) and mannose receptor, and this correlated with an increase in proinflammatory cytokine production after stimulation with the TLR4 ligand lipopolysaccharide. The heterologous production of Th1 (IFN-γ) and Th17 (IL-17 and IL-22) immune responses to nonmycobacterial stimulation remained strongly elevated even 1 year after BCG vaccination. In conclusion, BCG induces sustained changes in the immune system associated with a nonspecific response to infections both at the level of innate trained immunity and at the level of heterologous Th1/Th17 responses.

Fig. 1

BCG vaccination increased the heterologous Th1 responses. PBMCs isolated from 18 volunteers before and after (2 weeks, 3 months and 1 year) vaccination were stimulated in vitro with sonicated MTB (a), heat-killed C. albicans yeast (b) and S. aureus (c). IFN-γ production was assessed in the supernatants by ELISA. * p < 0.05; ** p < 0.01.

Fig. 2

BCG induces long-lasting heterologous Th17 responses. PBMCs isolated from 18 volunteers before and after (2 weeks, 3 months and 1 year) vaccination were stimulated in vitro with sonicated MTB (a, d), heat-killed C. albicans yeast (b, e) and S. aureus (c, f). IL-17 (a-c) and IL-22 (d-f) production was assessed by ELISA in the supernatants. * p < 0.05; ** p < 0.01; *** p < 0.005.

Fig. 3

Effect of BCG on innate immune cytokines. PBMCs isolated from 18 volunteers before and after (2 weeks, 3 months and 1 year) vaccination were stimulated in vitro with sonicated MTB (a), heat-killed C. albicans yeast (b) and LPS (c, d). TNFα (a-c) and IL-1β (d) production was assessed by ELISA in the supernatants. * p < 0.05; ** p < 0.01.

Fig. 4

BCG alters the phenotype of circulating monocytes in healthy volunteers. Average surface expression levels of activation markers CD14+ (a) and CD11b (b), TLR4 (c) and TLR2 (d), and C-type lectin receptors MR (e) and dectin-1 (f) within the CD14+ monocytes population isolated from 18 volunteers before and after BCG vaccination. * p < 0.05; ** p < 0.01; *** p < 0.005.