A role for LFA‐1 in delaying T‐lymphocyte egress from lymph nodes

Lymphocytes use the integrin leukocyte function‐associated antigen‐1 (LFA‐1) to cross the vasculature into lymph nodes (LNs), but it has been uncertain whether their migration within LN is also LFA‐1 dependent. We show that LFA‐1 mediates prolonged LN residence as LFA‐1^?/? CD4 T cells have significantly decreased dwell times compared with LFA‐1^+/+ T cells, a distinction lost in hosts lacking the major LFA‐1 ligand ICAM‐1. Intra‐vital two‐photon microscopy revealed that LFA‐1^+/+ and LFA‐1^?/? T cells reacted differently when probing the ICAM‐1‐expressing lymphatic network. While LFA‐1^+/+ T cells returned to the LN parenchyma with greater frequency, LFA‐1^?/? T cells egressed promptly. This difference in exit behaviour was a feature of egress through all assessed lymphatic exit sites. We show that use of LFA‐1 as an adhesion receptor amplifies the number of T cells returning to the LN parenchyma that can lead to increased effectiveness of T‐cell response to antigen. Thus, we identify a novel function for LFA‐1 in guiding T cells at the critical point of LN egress when they either exit or return into the LN for further interactions.     

Transiently Reduced PI3K/Akt Activity Drives the Development of Regulatory Function in Antigen-Stimulated Na?ve T-Cells

Regulatory T-cells (T_regs) are central for immune homeostasis and divided in thymus-derived natural T_regs and peripherally induced iT_reg. However, while phenotype and function of iT_regs are well known, a remarkable lack exists in knowledge about signaling mechanisms leading to their generation from naïve precursors in peripheral tissues. Using antigen specific naïve T-cells from mice, we investigated CD4+ CD25+ FoxP3- iT_reg induction during antigen-specific T-cell receptor (TCR) stimulation with weak antigen presenting cells (APC). We show that early signaling pathways such as ADAM-17-activation appeared similar in developing iT_reg and effector cells (T_eff) and both initially shedded CD62-L. But iT_reg started reexpressing CD62-L after 24 h while T_eff permanently downmodulated it. Furthermore, between 24 and 72 hours iT_reg presented with significantly lower phosphorylation levels of Akt-S473 suggesting lower activity of the PI3K/Akt-axis. This was associated with a higher expression of the Akt hydrophobic motif-specific phosphatase PHLPP1 in iT_reg. Importantly, the lack of costimulatory signals via CD28 from weak APC was central for the development of regulatory function in iT_reg but not for the reappearance of CD62-L. Thus, T-cells display a window of sensitivity after onset of TCR triggering within which the intensity of the PI3K/Akt signal controls entry into either effector or regulatory pathways.