Top Reads

In this Top Read, Cimpean et al. (p. 1481) demonstrate how IL-15 exposure primes NK cells for IFN-γ transcription. NK cells were incubated with either low-dose (LD) or high-dose (HD) IL-15 prior to NK1.1 receptor stimulation. Only the HD IL-15 primed NK cells increased the transcription of Ifng above control levels, whereas inhibitors of either mTOR or glycolysis decreased Ifng transcription. Global chromatin access was increased following HD IL-15 priming in NK cells, however, the accessibility at the Ifng locus was unchanged with IL-15 exposure. RNA sequencing corroborated large-scale transcriptional changes that occurred with IL-15 priming in NK cells, and identified c-Myc in NK cells that were capable of Ifng transcription, although c-Myc was not required for transcription. These data show how IL-15 exposure changes NK cell networks, alters Ifng transcription, and induces metabolic changes in NK cells upon receptor stimulation.

Transcriptomics was used to show how macrophages alter their immunometabolic pathways in response to an accumulation of intracellular lipids in this Top Read by Ting et al. (p. 1561). Macrophages with high intracellular lipid content downregulated inflammatory, hypoxia, and cholesterol metabolism pathways concurrently upregulating pathways for antioxidants and fatty acid oxidation. LPS-induced glycolysis was suppressed in macrophages with accumulated lipids. Lipid accumulation also enhanced LPS-induced Nrf-2–mediated antioxidative defense, which destabilized HIF-1α. This destabilization shifted NADPH consumption from HIF-1α–regulated apoenzymes to those regulated by Nrf-2 to maintain inflammatory responses. Finally, foamy macrophages derived from atherosclerotic mice and human aorta displayed metabolic profiles similar to those from in vitro studies. Together, these studies show how lipid accumulation alters the metabolic pathways of macrophages and leads to altered immune responses.

In this Top Read, Hastey et al. (p. 1540) elucidated the role of IgM during Borrelia burgdorferi infection. IgM remained elevated above control levels months after B. burgdorferi infection, and antibiotics during infection did not decrease IgM levels in the treated mice. In mice lacking CD40L, IgM levels were similar to wild type controls, indicating that the IgM production was T cell independent. Conventional lymph node B cells, were shown to produce the B. burgdorferi–specific IgM. Purified IgM from infected mice provided passive protection from B. burgdorferi infection when injected into naive mice. However, whole serum from mice that are unable to secrete IgM also provided passive protection, suggesting factors in addition to IgM play a significant role in serum-mediated passive immune protection. IgM also played a significant role in controlling B. burgdorferi in the blood but unsuccessfully controlled infection of the tissue. Finally, vaccinating B. burgdorferi–infected mice primed the humoral response to produce influenza-specific IgM rather than IgG produced in the uninfected animals. Together these data suggest that B. burgdorferi infection skews the humoral response toward the production of IgM, providing some early protection, but is inefficient in controlling infection once the infection has spread to the tissues.