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Abstract
Activated chemokine receptor initiates inside-out signaling to transiently trigger activation of integrins, a process involving multiple components that have not been fully characterized. Here we report that GM-CSF/IL-3/IL-5 receptor common beta-chain-associated protein (CBAP) is required to optimize this inside-out signaling and activation of integrins. First, knockdown of CBAP expression in human Jurkat T cells caused attenuated CXC chemokine ligand-12 (CXCL12)-induced cell migration and integrin α4β1- and αLβ2-mediated cell adhesion in vitro, which could be rescued sufficiently upon expression of murine CBAP proteins. Freshly isolated CBAP-deficient primary T cells also exhibited diminution of chemotaxis toward CC chemokine ligand-21 (CCL21) and CXCL12, and these chemokines-induced T-cell adhesions in vitro. Adoptive transfer of isolated naive T cells demonstrated that CBAP deficiency significantly reduced lymph node homing ability in vivo. Finally, migration of T cell-receptor–activated T cells induced by inflammatory chemokines was also attenuated in CBAP-deficient cells. Further analyses revealed that CBAP constitutively associated with both integrin β1 and ZAP70 and that CBAP is required for chemokine-induced initial binding of the talin-Vav1 complex to integrin β1 and to facilitate subsequent ZAP70-mediated dissociation of the talin-Vav1 complex and Vav1 phosphorylation. Within such an integrin signaling complex, CBAP likely functions as an adaptor and ultimately leads to activation of both integrin α4β1 and Rac1. Taken together, our data suggest that CBAP indeed can function as a novel signaling component within the ZAP70/Vav1/talin complex and plays an important role in regulating chemokine-promoted T-cell trafficking.
Highlights
Chemokine/chemokine receptor–mediated signals are implicated in regulating trafficking, which is important for maintaining homeostasis in peripheral lymphoid organs and triggering immune responses after infection
Upon entry of T lymphocytes into peripheral lymphoid tissues, especially lymph nodes (LNs) and Peyer’s patches, the process is tightly controlled by interaction between T cells and specialized vessels known as high endothelial venules, which express CC chemokine ligand-21 (CCL21), a ligand for the homeostatic CCchemokine receptor CCR7 [1,2]
common betachain-associated protein (CBAP) was first identified as a binding protein of the bc subunit in hematopoietic cells [27], whereas integrin b1 was found to associate with bc in endothelial cells and plays an important role during vasculogenesis and tumor angiogenesis [25,26], leading us to hypothesize that CBAP may be involved in integrin-related cellular function, such as cell adhesion and migration
Summary
Chemokine/chemokine receptor–mediated signals are implicated in regulating trafficking, which is important for maintaining homeostasis in peripheral lymphoid organs and triggering immune responses after infection. Among the signaling molecules involved, ZAP70, a T lymphocyte–specific Syk family kinase, was recently reported to play an important role in T-cell transendothelial migration [8] and directional chemotaxis in vitro [9] and to critically regulate integrin-dependent adhesion via control of phosphorylation of the guanine nucleotide exchange factor, Vav, which is specific for the small Rho family GTPase Rac; this phosphorylation causes dissociation of the Vav1-talin signal complex [10]. Overexpression of the constitutively active mutant RacV12 in a T-cell line enhances cell spreading and adhesion [15], whereas expression of a dominant-negative mutant of Rac, or Rac1-specific small interfering RNA, reduces CXCL12induced transendothelial migration [8] and adhesion in T-cell lines and human T lymphocytes [11]
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