title: 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.
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Johanneke
authors.initials: J
authors.lastname: Kleinnijenhuis
authors.forename: Jessica
authors.initials: J
authors.lastname: Quintin
authors.forename: Frank
authors.initials: F
authors.lastname: Preijers
authors.forename: Christine Stabell
authors.initials: CS
authors.lastname: Benn
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Cor
authors.initials: C
authors.lastname: Jacobs
authors.forename: Joke
authors.initials: J
authors.lastname: van Loenhout
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.forename: Peter
authors.initials: P
authors.lastname: Aaby
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Reinout
authors.initials: R
authors.lastname: van Crevel
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000328:Adult; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009161:Mycobacterium / Q000276:immunology / Q000502:physiology; D051192:Receptors, Pattern Recognition / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D014611:Vaccination; D055815:Young Adult
chemical_list: D001500:BCG Vaccine; D020381:Interleukin-17; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D051192:Receptors, Pattern Recognition; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma