CCL5-CCR5-mediated Apoptosis in T Cells

Abstract

CCL5 (RANTES (regulated on activation normal T cell expressed and secreted)) and its cognate receptor, CCR5, have been implicated in T cell activation. CCL5 binding to glycosaminoglycans (GAGs) on the cell surface or in extracellular matrix sequesters CCL5, thereby immobilizing CCL5 to provide the directional signal. In two CCR5-expressing human T cell lines, PM1.CCR5 and MOLT4.CCR5, and in human peripheral bloodderived T cells, micromolar concentrations of CCL5 induce apoptosis. CCL5-induced cell death involves the cytosolic release of cytochrome c, the activation of caspase-9 and caspase-3, and poly(ADP-ribose) polymerase cleavage. CCL5-induced apoptosis is CCR5-dependent, since native PM1 and MOLT4 cells lacking CCR5 expression are resistant to CCL5-induced cell death. Furthermore, we implicate tyrosine 339 as a critical residue involved in CCL5-induced apoptosis, since PM1 cells expressing a tyrosine mutant receptor, CCR5Y339F, do not undergo apoptosis. We show that CCL5-CCR5-mediated apoptosis is dependent on cell surface GAG binding. The addition of exogenous heparin and chondroitin sulfate and GAG digestion from the cell surface protect cells from apoptosis. Moreover, the non-GAG binding variant, ( 44 AANA 47 )-CCL5, fails to induce apoptosis. To address the role of aggregation in CCL5-mediated apoptosis, nonaggregating CCL5 mutant E66S, which forms dimers, and E26A, which form tetramers at micromolar concentrations, were utilized. Unlike native CCL5, the E66S mutant fails to induce apoptosis, suggesting that tetramers are the minimal higher ordered CCL5 aggregates required for CCL5-induced apoptosis. Viewed altogether, these data suggest that CCL5-GAG binding and CCL5 aggregation are important for CCL5 activity in T cells, specifically in the context of CCR5-mediated apoptosis.

Interactions of the Chemokine CCL5/RANTES with Medium-Sized Chondroitin Sulfate Ligands

“…Although heparan sulfate is often considered the major GAG species that interacts with chemokines, both CS and dermatan sulfate (DS) also have submicromolar affinities for CCL5 (Mizumoto et al, 2013), establishing CS as a relevant target for investigation. In fact, CS has been shown to be important for the CCL5/CCR5-mediated induction of T cell apoptosis (Murooka et al, 2006), and for CCL5-induced monocyte arrest (von Hundelshausen et al, 2005). The sulfation pattern of CS and DS are also simpler than heparan sulfate (HS) and Hp, making them more convenient materials for the isolation of oligomers with defined structure.…”

Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells

“…213 Upon binding to CCR5 on tumor infiltrating T lymphocytes, RANTES activates a CCR5-dependent apoptotic pathway that involves the release of cytochrome-c into the cytosol, activation of caspase-3 and caspase-9 pathways, and cleavage of poly ADPribose polymerase (PARP). 206,260,261 Hypoxia in the tumor microenvironment can induce strong release of RANTES, which promotes tumor migration. 262,263 In addition, RANTES in serum is associated with cancer clinical stage and tumor progression in several cancers (for review, see ref 264 264 ).…”

Correlation of CCR5 and NLRP3 gene polymorphisms with renal damage due to hepatitis C virus-related cryoglobulinemia

“…In addition, this locus has a close correlation with pulmonary infection. A previous study (16) reported that locus rs1799987 is a risk genotype that is related to the susceptibility of Chinese Han people to tuberculosis. However, it was mentioned in the paper of Carpenter et al (17) that locus rs1799987 is not related to the susceptibility to tuberculosis in adults in Peru, indicating that the locus has regional and racial differences.…”