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.

'Trained immunity: consequences for lymphoid malignancies

“…1 For instance, after BCG vaccination complex cytokine profiles are induced that include elevated T-helper (Th) 1 cytokines like IFNγ and also interleukin (IL)-4 (Th2), IL-17 (Th17), and IL-10. [30][31][32][33] These responses belong to the adaptive immune responses that facilitate and contribute to infection control and vaccination efficacy.…”

Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine

“…Studies in human adults have shown that BCG vaccination induces epigenetic modifications in monocytes that can persist for several months, resulting in improved functional capacity and higher responses to both M. tuberculosis and unrelated antigens (15). This phenomenon, which has been characterized as an aspect of "trained immunity," was not restricted to monocytes and macrophages that are the target cells for mycobacteria but was also extended to T cells (16). Therefore, it has been proposed that novel TB vaccine candidates should aim to preserve these unique features of BCG.…”

Trained innate immunity: a salient factor in the pathogenesis of neuroimmune psychiatric disorders

“…Kleinnijenhuis et al isolated monocytes from adult humans before and 2 weeks after BCG vaccination, and stimulated them ex vivo with BCG, S. aureus, C. albicans or LPS. 26 Post BCG vaccination, monocytes showed markedly enhanced production (up to sevenfold) of various proinflammatory cytokines, including IFN-γ, TNF-α and IL-1β upon homogenous and heterogeneous stimulation, relative to monocytes pre-BCG vaccination. This upregulation in proinflammatory function was accompanied by increased expression of various activation markers and PRRs, including CD11b, CD14 and TLR-4, and was still present 1 year after BCG vaccination.…”

“…This upregulation in proinflammatory function was accompanied by increased expression of various activation markers and PRRs, including CD11b, CD14 and TLR-4, and was still present 1 year after BCG vaccination. 26 Primary stimulation of NOD2, a PRR for mycobacteria, with the NOD2-specific ligand muramyl dipeptide, mimicked the training effects of BCG, which was prevented when inhibiting NOD2 during primary stimulation, as well as its downstream signaling pathway, Rip2 kinase. Such training effects were also seen in human monocytes following neonatal BCG vaccination.…”

“…16,20,21 This long-term memory effect can persist for months, and possibly years, and is not exclusive or specific to the type of primary immune-stimulating event. 26 Recent studies suggest that innate immune cells also retain longterm memory for non-infectious immunostimulatory challenges, such as stress. 27 Despite the widespread interest in immune function and psychiatric illness, there has been no exhaustive discussion relating to the implications of trained innate immunity on mental health pathology.…”