IL-7–dependent STAT1 activation limits homeostatic CD4+ T cell expansion
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
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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Research Article AIDS/HIV Immunology

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

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 4

STAT1 overexpression in T cells leads to activation of STAT1 and STAT5 in response to IL-7.

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STAT1 overexpression in T cells leads to activation of STAT1 and STAT5 i...
LN cells from WT (n = 10) and STAT1 Tg (n = 10) mice were analyzed by flow cytometry for expression of (A) t-STAT1 and (B) phosphorylated STAT1 and STAT5 after in vitro stimulation with rmIL-7 (1 ng/ml) in B cells (CD3– B220+), CD4+ (B220– CD3+ CD4+), and CD8+ (B220– CD3+ CD8+) T cells. Shaded histograms represent isotype control staining. The MFIs of t-STAT1, p-STAT1, and p-STAT5 in the different populations were compared between WT (black symbols) and STAT1 Tg (red symbols) mice using a nonparametric Mann-Whitney test. Data from 3 independent experiments, including an average of 3–4 mice per group per experiment, are presented as box and whisker plots showing the median MFI value bounded by the first and third quartiles in the box, with whiskers extending to the minimum and maximum values. (C) Gene set enrichment analysis (GSEA) histograms of IFN signature in STAT1 Tg versus WT CD4+ and CD8+ naive T cells stimulated with IL-7. The enrichment score (ES; y axis) reflects the degree to which IFN signature was enriched in STAT1 Tg vs. WT T cells. Each solid bar represents 1 gene within IFN signature. The heat-map image illustrates the gene expression levels of the leading edge subset. The normalized enrichment score (NES) and false discovery rate (FDR) q value are indicated.