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 2

Lymphopenia-induced STAT1 upregulation in T cells leads to activation of STAT1 and STAT5 in response to IL-7.

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Lymphopenia-induced STAT1 upregulation in T cells leads to activation of...
Lymphoreplete B6 CD45.1 (B6 host, n = 7) and lymphopenic RAG–/– CD45.1 (RAG–/– host, n = 11) mice were injected i.v. with 10 × 106 of CellTrace Violet–labeled (CTV-labeled) lymph node (LN) cells from congenic B6 CD45.2 mice. Analysis of transferred cells was performed on day 7 after transfer. The expression levels of STAT1 and activated p-STAT1 and p-STAT5 of donor T cells were evaluated by flow cytometry in LNs as function of CTV fluorescence after in vitro stimulation with rmIL-7 (1 ng/ml). Donor T cells undergoing slow proliferation (SP, CTV+ cells gated in blue) and fast proliferation (FP, CTV– cells gated in green) after transfer into RAG–/– hosts were analyzed separately. (A) The percentages of donor T cells CTV+ t-STAT1high, CTV– t-STAT1high, and CTV– t-STAT1low are indicated. The MFIs of t-STAT1 in CD4+ and CD8+ donor T cells 7 days after adoptive transfer into lymphoreplete B6 (black symbols) and lymphopenic RAG–/– hosts undergoing SP (blue symbols) or FP (green symbols) were compared using a nonparametric Mann-Whitney test. (B) The percentages of donor T cells CTV+ p-STAT1high, CTV+ p-STAT1low, CTV– p-STAT1high, and CTV– p-STAT1low and CTV+ p-STAT5high, CTV+ p-STAT5low, CTV– p-STAT5high, and CTV– p-STAT5low are indicated. The MFIs of p-STAT1 and p-STAT5 in CD4+ and CD8+ donor T cells after adoptive transfer into lymphoreplete B6 (black symbols) and lymphopenic RAG–/– hosts undergoing SP (blue symbols) or FP (green symbols) were compared using a nonparametric Mann-Whitney test. Data 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, from 3 independent experiments out of 3, including an average of 2–4 mice per group per experiment.