CXCR4 Physically Associates with the T Cell Receptor to Signal in T Cells

Abstract

SDF-1alpha (CXCL12) signaling via its receptor, CXCR4, stimulates T cell chemotaxis and gene expression. The ZAP-70 tyrosine kinase critically mediates SDF-1alpha-dependent migration and prolonged ERK mitogen-activated protein (MAP) kinase activation in T cells. However, the molecular mechanism by which CXCR4 or other G protein-coupled receptors activate ZAP-70 has not been characterized. Here we show that SDF-1alpha stimulates the physical association of CXCR4 and the T cell receptor (TCR) and utilizes the ZAP-70 binding ITAM domains of the TCR for signal transduction. This pathway is responsible for several of the effects of SDF-1alpha on T cells, including prolonged ERK MAP kinase activity, increased intracellular calcium ion concentrations, robust AP-1 transcriptional activity, and SDF-1alpha costimulation of cytokine secretion. These results suggest new paradigms for understanding the effects of SDF-1alpha and other chemokines on immunity.

Signal-Transducing Adaptor Protein-2 Regulates Stromal Cell-Derived Factor-1α-Induced Chemotaxis in T Cells

“…SDF-1 can guide the movement of immune cells in vivo, and it can induce tight adhesion of rolling cells to activated endothelial cells, followed by their subsequent transendothelial migration. SDF-1 also enhances T cell responses to Ag stimulation via the secretion of cytokines and the promotion of cell survival (31,32). In the present study, we have found that an adaptor molecule, STAP-2, is a novel regulator of SDF-1␣-induced chemotaxis of T cells.…”

Analysis of Phosphorylation-dependent Protein Interactions of Adhesion and Degranulation Promoting Adaptor Protein (ADAP) Reveals Novel Interaction Partners Required for Chemokine-directed T cell Migration

“…Also, when the TCR is fully phosphorylated in its cytoplasmic domains upon TCR stimulation, it will be the prime target for the tandem SH2 domains of ZAP70, which is, in this way, recruited to the membrane for further activation by Lck. However, after CXCR4 stimulation there is only a weak basal phosphorylation of the TCR complex, and ZAP70 is potentially recruited to different compartments (57); signaling molecules such as ADAP may provide the ITAM-like motifs that capture the ZAP70 SH2 domains under these conditions. Interestingly, we found the phosphatase STS-1 as a binding partner of ADAP-hSH3 N under oxidizing conditions.…”

“…However, availability of interacting molecules such as ZAP70 could also be the threshold-defining step, and it is worth noting that phosphorylation of the actin regulatory VAV1 depends on ZAP70, and is prominent after 5 min of CXCL12 stimulation (62). Longer stimulation times (Ͼ8 min) also lead to co-localization of CXCR4 and the TCR, thereby allowing CXCR4 to enhance TCR-specific signals (57). Under migratory conditions it is unlikely that such co-segregation of receptors is sustained; one possibility is that ADAP recruitment of ZAP70 prevents the pre-emptive binding of the kinase to small amounts of phosphorylated TCR.…”

Targeting CXCR4-dependent immunosuppressive Ly6C low monocytes improves antiangiogenic therapy in colorectal cancer

“…S6). Given that effector CD4 + and CD8 + T cells are known to express CXCR4 in some contexts (22,23), we measured the expression of CXCR4 on these lymphocytes. However, to our surprise, we observed only a negligible level of CXCR4 expression on T lymphocytes in the CRC microenvironment (Fig.…”