CCR5 expression levels influence NFAT translocation, IL-2 production, and subsequent signaling events during T lymphocyte activation

Jose F. Camargo, Marlon P. Quinones, Srinivas Mummidi, Sowmya Srinivas, Alvaro A. Gaitan, Kazi Begum, Fabio Jimenez, Scott VanCompernolle, Derya Unutmaz, Seema S. Ahuja, Sunil K. Ahuja

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

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-Δ32/ Δ32 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.

Original languageEnglish (US)
Pages (from-to)171-182
Number of pages12
JournalJournal of Immunology
Volume182
Issue number1
DOIs
StatePublished - Jan 1 2009

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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