Flip side of the coin: IFNg-induced trained immunity in non-immune cells
Lars Jansen group
Innate immunity involves an acute, mostly non-specific cellular response to infection. Unlike adaptive immunity that mounts a specific long-lasting memory of infection, the innate immune system acts transiently. However, recent insights revealed that innate immune cells such as those in the monocyte linage can maintain a "primed" state (1). Such so-called "trained immunity" allows cells to maintain a poised state following initial pathogen infection or exposure to inflammatory signals and show heighten resistance to intracellular pathogens such as viruses (2). Improperly regulated trained immunity impacts chronic inflammation in cancer, autoimmune pathologies or infectious diseases. Even though trained immunity has been described as a phenomenon at the wholeorganism level in mice and patients with a strong emphasis on immune cells, how priming works at the molecular level in is largely unknown.Central to the cellular response is a phenomenon called "long-term transcriptional memory" where pathogen signals or cytokines activate gene expression which leads to a primed-transcriptional state. Such priming results in a faster and stronger transcriptional response upon a second exposure, even following several cell division cycles in the absence of the signal, potentially underpinning trained immunity. We recently discovered a set of human innate immune target genes that are strongly primed by the cytokine Interferon gamma (IFNg) in non-immune cells (3). Following priming, in the absence of ongoing transcription, cells maintain a memory of exposure as revealed by a strong reactivation of these genes up to two weeks later, under continued proliferation. The mechanisms of priming are unknown, but, based on the evidence from other memory systems (4) and our current data, they involve changes in chromatin structure at IFN target genes. Here, I present the recent discoveries behind the identification of chromatin regulators in IFNg-induced transcriptional memory.
Keywords: Chromatin, Epigenetics, Innate immunity, Interferon, Transcriptional memory