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IL-7–dependent STAT1 activation limits homeostatic CD4+ T cell expansion
Cecile Le Saout, … , H. Clifford Lane, Marta Catalfamo
Cecile Le Saout, … , H. Clifford Lane, Marta Catalfamo
Published November 16, 2017
Citation Information: JCI Insight. 2017;2(22):e96228. https://doi.org/10.1172/jci.insight.96228.
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Research Article AIDS/HIV Immunology

IL-7–dependent STAT1 activation limits homeostatic CD4+ T cell expansion

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Abstract

IL-7 regulates homeostatic mechanisms that maintain the overall size of the T cell pool throughout life. We show that, under steady-state conditions, IL-7 signaling is principally mediated by activation of signal transducers and activators of transcription 5 (STAT5). In contrast, under lymphopenic conditions, there is a modulation of STAT1 expression resulting in an IL-7–dependent STAT1 and STAT5 activation. Consequently, the IL-7–induced transcriptome is altered with enrichment of IFN-stimulated genes (ISGs). Moreover, STAT1 overexpression was associated with reduced survival in CD4+ T cells undergoing lymphopenia-induced proliferation (LIP). We propose a model in which T cells undergoing LIP upregulate STAT1 protein, “switching on” an alternate IL-7–dependent program. This mechanism could be a physiological process to regulate the expansion and size of the CD4+ T cell pool. During HIV infection, the virus could exploit this pathway, leading to the homeostatic dysregulation of the T cell pools observed in these patients.

Authors

Cecile Le Saout, Megan A. Luckey, Alejandro V. Villarino, Mindy Smith, Rebecca B. Hasley, Timothy G. Myers, Hiromi Imamichi, Jung-Hyun Park, John J. O’Shea, H. Clifford Lane, Marta Catalfamo

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Figure 1

Increased STAT1 expression is associated with IL-7–dependent STAT1 phosphorylation.

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Increased STAT1 expression is associated with IL-7–dependent STAT1 phosp...
(A) Isolated CD4+ T cells from a healthy donor were cultured 3 days in media alone or rhIL-7 (10 ng/ml). After 3 days of culture, the cells were harvested, washed, and rested overnight to allow IL-7R reexpression (52). Rested cells were then stimulated in vitro with rhIL-7 (1 ng/ml) for 30 minutes, and cell lysates were analyzed by Western blotting with antibodies specific to p-STAT1, t-STAT1, p-STAT5, and t-STAT5. An antibody to actin was used to confirm even protein loading. Results are representative of at least 3 different donors. (B) PBMCs from healthy controls (HC, n = 22) and HIV-infected patients with viremia suppressed to < 50 copies/ml for median 17 months on cART (HIV+, n = 53) were analyzed for t-STAT1 and p-STAT1 levels in total CD4+ and CD8+ T cell populations. The relationship between the STAT1 phosphorylation after 30 minutes in vitro stimulation with rhIL-7 and t-STAT1 levels was assessed using a nonparametric Spearman test.

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