Project description:Clonal expansion and immunological memory are hallmark features of the mammalian adaptive immune response and essential for prolonged host control of pathogens. Recent work demonstrated that natural killer (NK) cells of the innate immune system also exhibit these adaptive traits during infection. Here we demonstrate that differentiating and ‘memory’ NK cells possess distinct chromatin accessibility states, and that their epigenetic profiles reveal a ‘poised’ regulatory program at the memory stage. Furthermore, we elucidate how individual STAT proteins differentially control epigenetic and transcriptional states early during infection. Finally, concurrent chromatin profiling of the canonical CD8+ T cell response against the same infection demonstrated parallel and distinct epigenetic signatures defining NK cells and CD8+ T cells. Overall, our study reveals the dynamic nature of epigenetic imprinting during the generation of innate and adaptive lymphocyte memory.
Project description:Exposure to pathogen-associated molecular patterns (PAMPs) induces an augmented, broad-spectrum antimicrobial response to subsequent infection, a phenomenon termed innate immune memory. This study examined the effects of treatment with β-glucan, a fungus-derived Dectin-1 ligand, and monophosphoryl lipid A (MPLA), a bacteria-derived TNS4 ligand, on innate immune memory with a focus on identifying common cellular and molecular pathways. Treatment with either PAMP prepared the innate immune system to respond more robustly to Pseudomonas aeruginosa infection in vivo by facilitating mobilization of innate leukocytes into blood, their recruitment to the site of infection, augmentation of microbial clearance and attenuation of cytokine production. Examination of macrophages ex vivo showed that metabolism, phagocytosis and respiratory burst were amplified by treatment with either agent, although MPLA more robustly augmented these activities and more effectively facilitated killing of bacteria. Both agents activated gene expression pathways in macrophages that control inflammation, antimicrobial functions and protein synthesis and suppressed pathways regulating cell division with MPLA more potently inducing global gene transcription. β-glucan treatment minimally modified macrophage differential gene expression in response to LPS challenge compared to control whereas MPLA attenuated the magnitude of the LPS-induced transcriptional response. These results show that b-glucan and MPLA similarly augment the innate response to infection in vivo. Yet, MPLA more potently induces alterations in macrophage metabolism, antimicrobial functions, gene transcription and the response to LPS.
Project description:Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished—training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer’s pathology, immune training exacerbates cerebral beta-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.
