Maintenance of homeostatic immune surveillance and development of effective adaptive immune responses require precise regulation of spatial and temporal lymphocyte trafficking throughout the body to ensure pathogen clearance and memory generation. Dysregulation of lymphocyte activation and migration can lead to impaired adaptive immunity, recurrent infections, and an array of autoimmune diseases and chronic inflammation. Central to the recruitment of T cells, integrins are cell surface receptors that regulate adhesion, signal transduction, and migration. With 24 integrin pairs having been discovered to date, integrins are defined not only by the composition of the heterodimeric pair but by cell-type specific expression and their ligands. Furthermore, integrins not only facilitate adhesion but also induce intracellular signaling and have recently been uncovered as mechanosensors providing additional complexity to the signaling pathways. Among several leukocyte-specific integrins, lymphocyte function-associated antigen-1 (LFA-1 or αLβ2; CD11a/CD18) is a key T cell integrin, which plays a major role in regulating T cell activation and migration. Adhesion to LFA-1’s ligand, intracellular adhesion receptor 1 (ICAM-1) facilitates firm endothelium adhesion, prolonged contact with antigen-presenting cells, and binding to target cells for killing. While the downstream signaling pathways utilized by LFA-1 are vastly conserved they allow for highly disparate responses. Here, we summarize the roles of LFA-1 and ongoing studies to better understand its functions and regulation.
T-helper (Th) cell differentiation drives specialized gene programs that dictate effector T cell function at sites of infection. Here, we have shown Th cell differentiation also imposes discrete motility gene programs that shape Th1 and Th2 cell navigation of the inflamed dermis. Th1 cells scanned a smaller tissue area in a G protein-coupled receptor (GPCR) and chemokine-dependent fashion, while Th2 cells scanned a larger tissue area independent of GPCR signals. Differential chemokine reliance for interstitial migration was linked to STAT6 transcription-factordependent programming of integrin a V b 3 expression: Th2 cell differentiation led to high a V b 3 expression relative to Th1 cells. Th1 and Th2 cell modes of motility could be switched simply by manipulating the amount of a V b 3 on the cell surface. Deviating motility modes from those established during differentiation impaired effector function. Thus, programmed expression of a V b 3 tunes effector T cell reliance on environmental cues for optimal exploration of inflamed tissues.
LFA-1 mediates T cell migration and their stable interaction with antigen-presenting cells, but how intracellular LFA-1 dynamically and spatially regulates T cell function is unclear. Capece et al. now demonstrate that intracellular LFA-1 in naive CD8+ T cells controls their asymmetric activation and differentiation into effector or memory T cells.
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