T-cell integrins: more than just sticking points

Abstract

T cells use integrins in essentially all of their functions. They use integrins to migrate in and out of lymph nodes and, following infection, to migrate into other tissues. At the beginning of an immune response, integrins also participate in the immunological synapse formed between T cells and antigen-presenting cells. Because the ligands for integrins are widely expressed, integrin activity on T cells must be tightly controlled. Integrins become active following signalling through other membrane receptors, which cause both affinity alteration and an increase in integrin clustering. Lipid raft localization may increase integrin activity. Signalling pathways involving ADAP, Vav-1 and SKAP-55, as well as Rap1 and RAPL, cause clustering of leukocyte function-associated antigen-1 (LFA-1; integrin αLβ2). T-cell integrins can also signal, and the pathways dedicated to the migratory activity of T cells have been the most investigated so far. Active LFA-1 causes T-cell attachment and lamellipodial movement induced by myosin light chain kinase at the leading edge, whereas RhoA and ROCK cause T-cell detachment at the trailing edge. Another important signalling pathway acts through CasL/Crk, which might regulate the activity of the GTPases Rac and Rap1 that have important roles in T-cell migration.

Pseudoapoptosis Induced by Brief Activation of ATP-gated P2X7 Receptors

“…However, when both extracellular calcium influx and intracellular calcium increases were prevented, a non-zeiotic type of blebbing occurred, which was completely blocked by the ROCK-1 inhibitor, Y-27632. An unmasking of this signaling cascade in the absence of calcium might well be expected as the RhoA/ROCK-1 pathway is known to be calcium-independent (35,37,42). Thus, we can conclude that P2X 7 R activation mediates membrane blebbing by (at least) two distinct paths, a calcium-dependent mechanism and a calcium-independent RhoA/ROCK-1 mechanism.…”

Opposing roles for RhoH GTPase during T-cell migration and activation

“…Chemokine and TCR signals induce the open conformation of LFA-1, via inside-out signaling (2). A significant body of primary literature supports the presence of common intermediates between the inside-out signaling pathways downstream of chemokine and TCR-induced activation of LFA-1, including CAS and Rap1 activation (Fig.…”

“…It has been speculated that RhoH may interfere with Rap1 activation making this a probable target for modulating both chemokine and TCR-induced activation of LFA-1 (8). Importantly, RhoH, like Cbl-b, has a negative impact on LFA-1-mediated adhesion (2). RhoH also inhibits several effector functions of Rho family small GTPases, such as NF-kB activation induced by Rac1 and cdc42 and RhoA and p38MAPK activation by Rac1 and cdc42 (14), yet these would not directly impact inside-out signaling to induce LFA-1 activation.…”

“…The crucial role of Rap1 in LFA-1 activation during T-cell migration and priming is well established (2,5,19). It was, however, unexpected to find disparate downstream effects of RhoH overexpression on chemokine and TCR-mediated Rap1 activation.…”

“…Integrin-mediated adhesion is needed for extravasation through high endothelial venules (HEVs) and intranodal migration during which APC scanning occurs (2). The fibroblastic reticular cell network serves as a matrix upon which T cells migrate and expresses ICAM-1 as well as CCL21, CCL19, and CXCL12 (3).…”