CCR5 Expression Levels Influence NFAT Translocation, IL-2 Production, and Subsequent Signaling Events during T Lymphocyte Activation

Abstract

Ligands of CCR5, the major coreceptor of HIV-1, costimulate T lymphocyte activation. However, the full impact of CCR5 expression on T cell responses remains unknown. Here, we show that compared with CCR5 ؉/؉ , T cells from CCR5 ؊/؊ mice secrete lower amounts of IL-2, and a similar phenotype is observed in humans who lack CCR5 expression (CCR5-⌬32/⌬32 homozygotes) as well as after Ab-mediated blockade of CCR5 in human T cells genetically intact for CCR5 expression. Conversely, overexpression of CCR5 in human T cells results in enhanced IL-2 production. CCR5 surface levels correlate positively with IL-2 protein and mRNA abundance, suggesting that CCR5 affects IL-2 gene regulation. Signaling via CCR5 resulted in NFAT transactivation in T cells that was blocked by Abs against CCR5 agonists, suggesting a link between CCR5 and downstream pathways that influence IL-2 expression. Furthermore, murine T cells lacking CCR5 had reduced levels of intranuclear NFAT following activation. Accordingly, CCR5 expression also promoted IL-2-dependent events, including CD25 expression, STAT5 phosphorylation, and T cell proliferation. We therefore suggest that by influencing a NFAT-mediated pathway that regulates IL-2 production and IL-2-dependent events, CCR5 may play a critical role in T cell responses. In accord with our prior inferences from geneticepidemiologic studies, such CCR5-dependent responses might constitute a viral entry-independent mechanism by which CCR5 may influence HIV-AIDS pathogenesis.

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

“…As for CCR5 and it ligands, it has been shown that CCL5, via CCR5, is required for effective activation of CCR5, thus serving as costimulatory signals in T cell activation (20), and that this interaction signals via NFAT translocation leading to IL-2 production by CD4 + T cells (22). Our results showing that all three CCR5 ligands may intercompensate one another to effectively induce this signal, and thus, only concurrent targeted neutralization of all of them would inhibit CD4 + T cell proliferation (Fig.…”

“…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. The in vivo implications of these findings have never been explored.…”

Lysosomal phospholipase A2: A novel player in host immunity to Mycobacterium tuberculosis

“…Like TNF-α, CCL5 is produced by a wide variety of cells including macrophages in response to M. tuberculosis infection [25]. In addition to its chemotactic property attracting a number of immune cells including T cells and macrophages, CCL5 directly contributes to T-cell activation [26][27][28]. Thus, significantly abated CCL5 production in mLNs is likely to preclude T-cell priming and proliferation in LPLA 2 KO mice.…”

Immune reconstitution under antiretroviral therapy: the new challenge in HIV-1 infection

“…As the main HIV-1 coreceptor, C-C chemokine receptor type 5 (CCR5) is now recognized as a co-activation molecule at the surface of CD4 ϩ T cells, 62 it could be involved in immune activation and thereby in the rise in CD4 count. This could explain why the administration of a CCR5 antagonist resulted in a decrease in T-cell activation.…”