Calcium Signaling through the β2-Cytoplasmic Domain of LFA-1 Requires Intracellular Elements of the T Cell Receptor Complex

Abstract

The ␤ 2 integrin LFA-1 is an important cell-cell adhesion receptor of the immune system. Evidence suggests that the molecule also participates in signaling and costimulatory function. We show here that clustering of the intracellular domain of the ␤ 2 chain but not of the ␣ L -or ␤ 1 -cytoplasmic domains, respectively, triggers intracellular Ca 2؉ mobilization in Jurkat cells. A ␤ 2 -specific NPXF motif, located in the C-terminal portion of the ␤ 2 tail, is required for Ca 2؉ signaling, and we show that this motif is important for the induction of allospecific target cell lysis by cytotoxic T cells in vitro. Significantly, the Ca 2؉ -signaling capacity of the ␤ 2 integrin is abrogated in T cells that do not express the T cell receptor but may be reconstituted by co-expression of the T cell receptor-chain. Our data suggest a specific function of the cytoplasmic domain of the ␤ 2 integrin chain in T cell signaling.

Leukocyte Function Antigen-1, Kindlin-3, and Calcium Flux Orchestrate Neutrophil Recruitment during Inflammation

“…Our data demonstrates that Kindlin-3 recruitment to the β 2 -cytodomain is necessary for optimum calcium flux by physically linking LFA-1 bond clusters and Orai1 at a point upstream of Talin-1 association. Recent evidence indicates that a β 2 -specific NP X F motif is essential for triggering calcium signaling in Jurkat cells and our data suggests that Kindlin-3 may function as the scaffold protein linking the β 2 -integrin cytodomain to Orai1 during intracellular calcium mobilization (53). There are a number of cytoplasmic proteins that Kindlin-3 may interact with to activate calcium influx including STIM1, an ER luminal calcium sensor that facilitates clustering and spatial recruitment of Orai1 proximal to the ER (54, 55).…”

β2 Integrin Induces TCRζ–Syk–Phospholipase C-γ Phosphorylation and Paxillin-Dependent Granule Polarization in Human NK Cells

“…In Jurkat T cells, clustering of the integrin β 2 cytoplasmic tail results in calcium flux, and this response is defective in cells lacking the TCR ζ chain (54). This study was performed using overexpressed fusion proteins, rather than intact integrin chains, but it highlights a possible functional tie between β 2 integrins and the TCR ζ chain in T cells.…”

Signal Transduction During Activation and Inhibition of Natural Killer Cells

“…Signaling by β2 and β3 integrins in neutrophils, platelets, and myeloid cells requires Syk and an ITAM-containing transmembrane adapter molecule, which can be either DAP12 or the FcR γ chain (Jakus et al ., 2007). Similarly, calcium signaling through the β2 cytoplasmic tail of LFA-1 in T cells required the TCR, a requirement that could be fulfilled by the TCR ζ chain alone (Sirim et al ., 2001). It remains to be seen whether these unusual signaling properties contribute to the unique ability of LFA-1 to trigger granule polarization in primary NK cells.…”