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* Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System, San Antonio, TX 78229 and Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229;
Department of Psychiatry and Center for Bipolar Illness Intervention in Hispanic Communities, The University of Texas Health Science Center, San Antonio, TX 78229;
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37201;
Department of Microbiology and Department of Pathology, New York University School of Medicine, New York, NY 10016; and
¶ Departments of Microbiology and Immunology and Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229
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 genetic-epidemiologic studies, such CCR5-dependent responses might constitute a viral entry-independent mechanism by which CCR5 may influence HIV-AIDS pathogenesis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Veterans Administration Center on AIDS and HIV infection of the South Texas Veterans Health Care System, a MERIT (R37046326) and other awards (AI043279 and MH069270) from the National Institutes of Health to S.K.A., and separate Merit Review grants from the Department of Veterans Affairs to S.K.A., S.S.A., and S.M. This work was also supported by a National Institutes of Health grant to D.U. (RO1-AI49131). S.K.A. is a recipient of the Elizabeth Glaser Scientist Award and the Burroughs Wellcome Clinical Scientist Award in Translational Research. M.P.Q. acknowledges support by the Stanley Research Foundation and a Young Investigator NARSAD award.
2 M.P.Q. and S.M. contributed equally to this study.
3 Address correspondence and reprint requests to Dr. Sunil K. Ahuja, University of Texas Health Science Center, 7703 Floyd Curl Drive, Room 5.009R, San Antonio, TX 78229. E-mail address: ahujas{at}uthscsa.edu
4 Abbreviations used in this paper: WT, wild type; PP, Peyer’s patches.
5 The online version of this article contains supplemental material.
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