• Johanneke Kleinnijenhuis, Jessica Quintin, Frank Preijers, Leo A B Joosten, Daniela C Ifrim, Sadia Saeed, Cor Jacobs, Joke van Loenhout, Dirk de Jong, Hendrik G Stunnenberg, Ramnik J Xavier, Jos W M van der Meer, Reinout van Crevel, and Mihai G Netea.
• Department of Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
• Proc. Natl. Acad. Sci. U.S.A. 2012 Oct 23;109(43):17537-42.

AbstractAdaptive features of innate immunity, recently described as "trained immunity," have been documented in plants, invertebrate animals, and mice, but not yet in humans. Here we show that bacille Calmette-Guérin (BCG) vaccination in healthy volunteers led not only to a four- to sevenfold increase in the production of IFN-γ, but also to a twofold enhanced release of monocyte-derived cytokines, such as TNF and IL-1β, in response to unrelated bacterial and fungal pathogens. The enhanced function of circulating monocytes persisted for at least 3 mo after vaccination and was accompanied by increased expression of activation markers such as CD11b and Toll-like receptor 4. These training effects were induced through the NOD2 receptor and mediated by increased histone 3 lysine 4 trimethylation. In experimental studies, BCG vaccination induced T- and B-lymphocyte-independent protection of severe combined immunodeficiency SCID mice from disseminated candidiasis (100% survival in BCG-vaccinated mice vs. 30% in control mice). In conclusion, BCG induces trained immunity and nonspecific protection from infections through epigenetic reprogramming of innate immune cells.

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