CXCR4–CCR5: A couple modulating T cell functions

Abstract

Chemokines and their receptors direct leukocyte migration among blood, lymph and tissues. Evidence has recently accumulated that, besides their chemotactic functions, chemokine receptors are highly versatile players that fine tune immune responses. During human T cell activation by antigen-presenting cells, the chemokine receptors CCR5 and CXCR4 are recruited into the immunological synapse, where they deliver costimulatory signals. However, the molecular mechanisms allowing signaling versatility of chemokine receptors are unknown. Here, we describe the functional interaction between CXCR4 and CCR5 to exert specific biological functions and modulate T lymphocyte responses. We demonstrate that simultaneous expression and cooperation between CCR5 and CXCR4 are required for chemokine-induced T cell costimulation at the immunological synapse. In addition, we provide evidence for a physical association of the two receptors in a signaling complex that activates distinct T cell functions. We suggest that cooperation between receptors represents one key strategy for the functional plasticity of chemokines.chemokine receptors ͉ heterodimerization ͉ T cell costimulation T he immune system is able to mount an immune response against antigens present in the body at very low concentrations and, at the same time, to discriminate precisely between an infectious stimulus and a noninfectious one. During T cell activation, this sensitivity and specificity are achieved by mechanisms of sustained interactions with antigen-presenting cells (APCs) as well as by tunable activation thresholds and signal modulation (1). Thus, in addition to the interaction between the T cell receptor (TCR) and its ligand, T cell activation depends on accessory signals delivered by costimulatory molecules. CD28 is one of the most important costimulatory receptors for T cell priming in lymph nodes, but the costimulatory signals for effector T cells in the inflammatory microenvironment are less defined.Chemokines are small cytokines with selective chemoattractant properties coordinating tissue homeostasis and inf lammation. Besides their chemotactic functions, chemokines are involved in several biological and physiopathological processes. Thus, deregulated expression of chemokines and their receptors is involved in the development of autoimmunity, chronic inf lammation, immunodeficiency and cancer (2, 3). The broad range of activities displayed by chemokines is the consequence of multiple signaling pathways induced by chemokine receptors-seven-transmembrane molecules coupled to heterotrimeric G proteins (4).In T lymphocytes, the chemokine receptor CXCR4 is constitutively expressed and regulates T cell migration along gradients of the chemokine CXCL12. In contrast, CCR5 is expressed in activated T cells only and directs their migration along CCL3, CCL4 and CCL5 gradients. CXCR4 and CCR5 receptors are involved in several pathological processes, including autoimmunity, cancer, and HIV infection (3). We recently demonstrated that during T cell stimulation CCR5 ...

A Fusion Protein Encoding the Second Extracellular Domain of CCR5 Arrests Chemokine-Induced Cosignaling and Effectively Suppresses Ongoing Experimental Autoimmune Encephalomyelitis

“…In a recent study, Molon et al (20) showed that signals transduced by CCL5, via CCR5, are required for effective T cell activation. Subsequently, Contento et al (21) showed that during T cell activation by APCs, the chemokine receptors CCR5 and CXCR4 are recruited into the immunological synapse, where they deliver costimulatory signals mediated by their hetro-oligomerization. Very recently, Camargo et al (22) showed that the interaction between CCR5 and its ligands induces signals via NFAT translocation, leading to IL-2 production by CD4 + T cells, and that IL-2 production is highly related to CCR5 expression.…”

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120IIIBbinding to the cell surface

“…This fact is the case of the two main HIV-1 coreceptors, CXCR4 and CCR5. When coexpressed on a cell and in the absence of ligands, these two receptors form heterodimers (39,40,44) that appear to modulate lymphocyte functions (40). This effect is compatible with the consensus for the G protein-coupled receptors (GPCR), which considers heteromers as entities whose function differs from that of the individual receptors (45).…”

“…(18,19,26,35,37,38). Although heterodimer stabilization is associated with specific signaling events (39)(40)(41) and with modulation of individual receptor activity (36,42,43), the functional relevance of these complexes remains unclear. This fact is the case of the two main HIV-1 coreceptors, CXCR4 and CCR5.…”

Heteromerization of chemokine (C-X-C motif) receptor 4 with α1A/B-adrenergic receptors controls α1-adrenergic receptor function

“…CXCR4 has been shown to associate with multiple chemokine receptors in various expression systems (3,(25)(26)(27)(28). ARs are also known to be able to form heteromeric receptor complexes (29)(30)(31)(32)(33)(34)(35), and recent evidence suggests that AR may also be able to form heteromeric complexes with chemokine receptors (36)(37)(38).…”