Naive T cells spend their lifespan circulating from the blood to lymphatic organs in search of cognate antigen presented by antigen-presenting cells (APCs) and then returning to the blood via the thoracic duct in a cyclical fashion. Successful expansion and differentiation of naive CD8+ T cells is dependent on the ability of cells to precisely localize with APCs in secondary lymphoid organs to form stable and prolonged interactions upon antigen recognition and T cell receptor (TCR) activation (Kaech et al., 2002; Cronin and Penninger, 2007; Chen and Flies, 2013). To undergo further T cell expansion and differentiation, T cells require additional stimuli from APCs and lymphatic cells that reside within niches in secondary lymphoid organs. Therefore, recirculation through lymph nodes, interactions with APCs, and localization to distinct immune niches are likely to impact CD8+ T cell division and differentiation. A key molecule regulating these processes is the integrin lymphocyte function–associated antigen 1 (LFA-1).

Adhesive force generated by LFA-1 ligation is essential for initial T cell entry into the lymph node through high endothelial venules (Weber et al., 2001) and subsequently T cell retention through interaction with the lymphatic stroma and APCs (Smith et al., 2003, 2007; Katakai et al., 2013). LFA-1 knockout (KO) T cells pass through the lymph node more rapidly and are three times more likely to exit (Reichardt et al., 2013). Enhanced LFA-1 adhesiveness is equally important for the maintenance of the immunological synapse and the signal integration