LFA-1 in T cell priming, differentiation, and effector functions

LFA-1 is a mechanosensitive adhesion receptor that couples mechanical forces to fine-tune T cell migration, differentiation, and effector functions. LFA-1 outside-in signaling cascades are coupled to actin dynamics. The contributions of LFA-1 to tight T cell interactions with cognate antigen-presenting dendritic cells and other antigen‐presenting cells vary, and their significance to T cell co-stimulation, differentiation, and memory remains unclear. LFA-1 participates in homotypic T cell–T cell interactions that drive Th1 differentiation responses and the formation of T cell memory. LFA-1 signals license human T cells and monocytes for intrinsic complement C3 gene expression driving IFN-γ and IL-1β production, respectively. The kinase WNK1 and the phosphatase PTPN22 have emerged as novel biologically important regulators of LFA-1 signaling in health and disease. The integrin LFA-1 is crucial for T cell entry into mammalian lymph nodes and tissues, and for promoting interactions with antigen-presenting cells (APCs). However, it is increasingly evident that LFA-1 has additional key roles beyond the mere support of adhesion between T cells, the endothelium, and/or APCs. These include roles in homotypic T cell–T cell (T–T) communication, the induction of intracellular complement activity underlying Th1 effector cell polarization, and the support of long-lasting T cell memory. Here, we briefly summarize current knowledge of LFA-1 biology, discuss novel cytoskeletal regulators of LFA-1 functions, and review new aspects of LFA-1 mechanobiology that are relevant to its function in immunological synapses and in specific pathologies arising from LFA-1 dysregulation. The integrin LFA-1 is crucial for T cell entry into mammalian lymph nodes and tissues, and for promoting interactions with antigen-presenting cells (APCs). However, it is increasingly evident that LFA-1 has additional key roles beyond the mere support of adhesion between T cells, the endothelium, and/or APCs. These include roles in homotypic T cell–T cell (T–T) communication, the induction of intracellular complement activity underlying Th1 effector cell polarization, and the support of long-lasting T cell memory. Here, we briefly summarize current knowledge of LFA-1 biology, discuss novel cytoskeletal regulators of LFA-1 functions, and review new aspects of LFA-1 mechanobiology that are relevant to its function in immunological synapses and in specific pathologies arising from LFA-1 dysregulation. failure to respond to antigen. protein complex that nucleates branched actin filaments. increased adhesion of LFA-1 due to receptor and ligand clustering. noncovalent bond the lifetime of which increases with applied tensile forces. E3 ubiquitin-protein ligase; negative regulator of tyrosine kinases. process by which CD4+ T cells promote clonal expansion and effector and memory differentiation of CD8+ T cells. individuals lacking cell surface expression of CD46. They develop hemolytic uremic syndrome and mount reduced Th1 and CTL responses. central region of the immunological synapse, contains the TCR- and associated signaling molecules docking protein implicated in cell adhesion. cytosolic adaptor protein regulating cell adhesion, spread, and migration. outer region of the immunological synapse, enriched in actin and negative regulators of TCR signaling, such as CD45. formin family protein; highly expressed in T cells. main stromal cell in LNs and the white pulp of the spleen. family of actin-nucleating proteins polymerizing linear actin filaments. members of the largest group of membrane receptors, which includes a subfamily of chemokine and chemoattractant receptors. occurs in the absence of antigen, particularly when T cells are transferred into hosts lacking T cells. high- and low-affinity ligands of LFA-1. cytokine that inhibits viral replication, activates numerous immune cells, induces MHC expression, and enhances antigen presentation. structured signaling platform/contact between different immune cells as well as between cytotoxic cells and their targets. occurs from chemokine receptors or the TCR, leading to LFA-1 activation. small, secreted protein released in response to type 1 interferons, recently shown to bind the extracellular domain of LFA-1 and induce outside-in signaling. short-lived adhesive contact between a T cell and APC driven by a cognate antigen–TCR interaction. front of a migrating cell. immunodeficiency disease caused by loss, or mutations in, the CD18 integrin chain. major integrin adhesion receptor in leukocytes. protein required for adhesion, migration, and proliferation. surface on which receptor ligands, such as ICAM-1 or anti-CD3 antibodies, have been printed into spatially separated zones with gaps in-between; used to study cell interactions. activated by the Rap1 signaling cascade through RAPL and Mst1/Mst2. peripheral region of the immunological synapse that LFA-1 and talin preferentially localize to. lipid kinase activated in response to TCR signaling and involved in LFA-1 activation, and T cell differentiation and proliferation phosphatase and negative regulator of multiple Src and Syk family kinases. small GTPase involved in controlling actin dynamics. small GTPase; required for LFA-1 avidity regulation. Treg cells, mainly CD4+, express the transcription factor FoxP3 and regulate or suppress other cells in the immune system. They are important in preventing autoimmunity. small GTPase involved in controlling actin dynamics. force created by blood flow; T cells need to overcome it to adhere to blood vessels and migrate into tissues. random cell motility that can include the mass recruitment of cells to a specific location. region in LNs and spleen enriched with T cells and DCs. actin binding protein. CD4+ T cells that produce proinflammatory cytokines, the main one being IFN-γ. Signals leading to Th1 polarization include IL-12 upon priming. particularly useful for interrogating cell surface molecular interactions and signaling (e.g., contact site between a cell and a glass coverslip or a supported lipid bilayer). measures mechanical forces on the surface of cells. membrane transfer between live cells that occurs following conjugation. posterior protrusion of a polarized cell during cell migration. actin nucleation promoting factor for the Arp2/3 complex. serine/threonine kinase, contributes to regulating T cell adhesion and migration.