FRC BioEnergetics · Functional dissection of metabolic checkpoints in lymph node fibroblastic reticular cells

Functional dissection of metabolic checkpoints in lymph node fibroblastic reticular cells

Efficient interactions between immune cells and antigens, necessary for the induction of immune responses, are initiated in secondary lymphoid organs (SLOs). Due to their unique position and structure, lymph nodes (LNs) collect extracellular fluids from peripheral tissues and display tissue and foreign antigens to circulating lymphocytes facilitating their activation. LNs structure and function are defined by fibroblastic reticular cells (FRCs) that build highly structured cellular scaffolds that, at the same time, provide migration clues (e.g., the chemokines CCL19, CCL21, CXCL13) and survival factors (e.g., the cytokines IL-7, IL-15) for incoming lymphocytes to position and to nurture them in defined microenvironmental niches. During the initiation of an immune response, the increased influx and extensive proliferation of activated lymphocytes require substantial changes in the form and function of the FRC infrastructure leading to a 10-fold increase in LN size. This process relies on the physical elasticity, cell stretching mechanisms, and proliferation of LN stromal cells. While the molecular signals inducing FRC activation and functional adaptation are being uncovered, bioenergetic demands of these cellular processes remain elusive. Cellular metabolism has emerged as one of the main processes underlying immune regulation. The possibility of manipulating the metabolic decisions of hematopoietic cells and those cells that control their activity offers new ways to optimize immune cell performance and treat immunological diseases. LN FRCs act as the significant coordinators of immune processes and need to change form and function to support LN growth and hematopoietic cell activation. The ability of cells to swiftly respond to such demands is energetically very expensive. FRC BioEnergetics has addressed the energetic needs of FRCs as coordinators of immune responsiveness and explored how metabolism regulates FRC function during the initiation of the immune response. Combining state-of-the-art genetic models for in vivo FRC targeting with high-throughput metabolic and transcriptional data profiling, we revealed swift rewiring of FRC metabolism upon lymph node swelling. To support immune response initiation, LN FRCs must increase mitochondria mass and membrane polarization and reshape the mitochondrial network using OPA1 protein. Genetic targeting of the proteins involved in mitochondrial fusion using in vivo models of bacterial infection and immune and metabolic assays revealed the critical role of the mitochondrial profusion protein OPA1 in regulating FRCs biology during infection. The inability of FRCs to rewire mitochondrial networks due to genetic deficiency in OPA1 abolished LN swelling reaction, thereby reducing overall immune responsiveness and pathogen control. This project has unveiled hitherto unknown regulatory circuits in cell-specific energetics that critically impinge on immune responsiveness and pathogen control, thereby opening new avenues for treating immunological diseases by targeting stromal cell metabolism.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз