Controlling Immunity and Inflammation through Integrin-Dependent Regulation of TGF-β

Integrins control spatiotemporal activation of latent TGF-β in extracellular matrix or cell-surface reservoirs. Integrin αvβ8 is constitutively active, binds latent TGF-β with extremely high affinity, and activates TGF-β using a chaperone protein. Integrin-dependent TGF-β activation by epithelial cells, dendritic cells, and fibroblasts instructs T cell behavior and maintains circulating and tissue-resident T cell populations. GARP/integrin αvβ8 cooperate to activate TGF-β on regulatory T cells, and blockade of this interaction enhances T cell responses against pathogens and cancer. Blocking integrin αvβ8 on dendritic cells and fibroblasts impairs TGF-β-dependent generation of Th17 cells, and reduces inflammatory disease in the lungs. TGF-β activation by integrins regulates gut-associated T cells, responses toward parasites, and is involved in metabolism, obesity, and diabetes. Integrins promote cell adhesion and migration, but also control local activation of latent transforming growth factor (TGF)-β contained in extracellular matrix or cell-surface reservoirs. Integrin-dependent activation of TGF-β has emerged as a crucial mechanism whereby tissue-borne cells instruct circulating and resident immune cells. Moreover, this regulation has wide pathophysiological implications in wound healing, tissue fibrosis, antibody production, pathogen clearance, inflammation, autoimmunity, cancer, and possibly metabolic disorders including diabetes. Here we review the spatiotemporal control of TGF-β activation by integrins, and its effects on immune cell signaling and function. We discuss the underlying molecular and cell-biological mechanisms, the implications for human health and disease, and possibilities for future therapeutic exploitation. Integrins promote cell adhesion and migration, but also control local activation of latent transforming growth factor (TGF)-β contained in extracellular matrix or cell-surface reservoirs. Integrin-dependent activation of TGF-β has emerged as a crucial mechanism whereby tissue-borne cells instruct circulating and resident immune cells. Moreover, this regulation has wide pathophysiological implications in wound healing, tissue fibrosis, antibody production, pathogen clearance, inflammation, autoimmunity, cancer, and possibly metabolic disorders including diabetes. Here we review the spatiotemporal control of TGF-β activation by integrins, and its effects on immune cell signaling and function. We discuss the underlying molecular and cell-biological mechanisms, the implications for human health and disease, and possibilities for future therapeutic exploitation. non-neuronal, supportive cells in the central nervous system. lymphocytes driving a humoral response by eliciting antibody formation. genetic recombination process in which B cells switch the production of a particular immunoglobulin isotype to another. phagocytic white blood cells that activate T cells through antigen presentation. transmembrane protein of the cadherin family mediating intercellular adhesion of epithelial cells. Meshwork of proteins surrounding cells in tissues. transmembrane receptor acting as a chaperone for immobilization and presentation of latent TGF-β. condition in which immune cells from a donor attack host cells after organ transplantation. large group of cytokines regulating immunity and inflammation. interleukin involved in mucosal defense against parasitic infections. proinflammatory interleukin that can activate various types of immune cells. SLC in complex with LTBP. peptide binding to inactive TGF-β. protein that anchors the SLC to the ECM. transmembrane receptor similar to GARP. phagocytic white blood cells that destroy pathogens and apoptotic cells. T cells that arise after encounter with an antigen and provide sustained immunity. resident macrophages of the central nervous system. circulating white blood cells that can differentiate into macrophages or dendritic cells. circulating, highly phagocytic white blood cells that rapidly clear bacterial and fungal infections. secondary lymphoid organs in the intestine containing B and T cells, where antigen presentation occurs and immune responses are elicited. receptor on T cells that, when activated, suppresses the proinflammatory activity of T cells. actively suppress T cell activation and thereby prevent autoimmunity. amino acid motif present in many integrin ligands including ECM proteins and LAP–TGF-β. Synonym for LAP–TGF-β. lymphocytes that, when activated, recognize and kill virus-infected and cancerous cells (CD8), or help other immune cells (CD4). cytokine with major effects on a variety of cells. serine/threonine kinase receptor specific for TGF-β that can transduce signals leading to gene expression. provide immunity against intracellular pathogens by producing IFNγ. provide immunity against parasites by producing IL-4, IL-5 and/or IL-13. provide immunity against extracellular bacteria or fungi by producing IL-17. transmembrane immune receptors that detect particular molecules derived from pathogens. experimental model for the study of inflammatory bowel disease. proinflammatory cytokine produced early during infection. disease characterized by high-blood sugar levels due to insufficient insulin production, often resulting from T cell-driven autoimmunity. disease characterized by high-blood sugar levels due to insulin resistance, often resulting from an unhealthy life-style. Controlling Immunity and Inflammation through Integrin-Dependent Regulation of TGF-β: (Trends in Cell Biology , 49–59, 2020)Nolte et al.Trends in Cell BiologyAugust 18, 2020In BriefThe publisher regrets that in the article the second initial of the first author was not published. The correct name is Martijn A. Nolte. Full-Text PDF