Transendothelial migration confers a survival advantage to activated T lymphocytes: role of LFA-1/ICAM-1 interactions

Abstract

SUMMARYThe clearance of activated T lymphocytes by apoptosis is an essential component in the resolution of the immune response; however, certain signals received within inflamed tissue may result in the persistence of activated T cells. Our previous work has shown that, when compared with resting cells, effector cells migrate more efficiently across endothelium, thus such cells may be selectively recruited to sites of inflammation. We hypothesized that transmigration of T cells across endothelium might influence cell survival. We have generated T cell lines by culturing in IL-2 following PHA activation. These T cell lines die rapidly by apoptosis when deprived of IL-2 (53·7 ± 4·0% survival after 24 h). In contrast, cells that have migrated across human umbilical vein endothelial cells (HUVEC) survived significantly better than control cells (80·3 ± 3·6%, n = 18, P < 0·001). Endothelial cell conditioned medium was also able to reduce apoptosis, but this effect was small when compared with the protective effect of transmigration. Culture of T lymphocytes on fibronectin, or RGD peptides, or in suspension with a range of chemokines active on T cells, including RANTES and lymphotactin had no effect on survival. In contrast, blocking LFA-l/ICAM-l interactions reduced the protective effect of transmigration (42·3 ± 6·7% reduction). Culture of activated T cells on immobilized ICAM-l alone also increased survival. These results indicate that signals received by activated T cells during extravasation can influence their subsequent survival within tissue, and implicates the involvement of LF A-l/ICAM-l interactions.

Endogenous tumor-reactive CD8+T cells are differentiated effector cells expressing high levels of CD11a and PD-1 but are unable to control tumor growth

“…This signaling is critical for the initiation of T-cell and NK cell cytotoxicity, leading to actin polymerization and granule polarization 31 , 32 . In addition, LFA-1 signaling stimulates the production of tumor necrosis factor α (TNFα) by activated NK cells, 33 as well as T-cell activation and survival 34 , 35 . Here, we found that tumor-reactive CD8 + T cells express increased levels of CD11a, suggesting an endogenous activation of CD8 + T cells by TAAs and an increased potential of CD8 + T cells to receive co-stimulatory signals from LFA-1.…”

Human macrophages rescue myoblasts and myotubes from apoptosis through a set of adhesion molecular systems

“…It is also involved in protection of T cells and retinal ganglion cells (Rose et al, 2000;Leussink et al, 2002;Leu et al, 2004). (2) ICAM-1 binding to LFA-1 (␣L␤2 integrin); this system mediates protective effects of endothelial cells to transmigrating lymphocytes (Borthwick et al, 2003). Its implication in support of bone marrow stromal cells to T cells (Winter et al, 2001), and of follicular dendritic cells to B cells (Koopman et al, 1994) has been also reported, but in vitro experiments have yielded somewhat discrepant results (Zen et al, 1996;Wang and Lenardo, 1997).…”

Triiodothyronine Modulates Differential Homing of Recent Thymic Emigrants to Peripheral Lymphoid Organs

“…independent specialized adhesion pathways. Accordingly, lymphocyte extravasation from blood into tissue is regulated by sequential interactions of selectins, chemokines and integrins with their ligands/counter receptors [13,14].…”

“…There are members of several families of adhesion molecules involved in lymphocyteendothelial interaction depending on the physiological step of lymphocyte homing. LFA-1 and VLA-4 are important integrin-type receptors for adhesion of lymphocytes, interacting with members of the Ig superfamily, ICAM-1 and VCAM respectively [13,14].…”