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

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. 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.