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 6

Adoptive transfer of STAT1 Tg T cells into lymphopenic RAG–/– mice leads to long-term impaired CD4+ T cell reconstitution.

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Adoptive transfer of STAT1 Tg T cells into lymphopenic RAG–/– mice leads...
Lymphopenic RAG–/– mice transferred with WT (n = 16) or STAT1 Tg (n = 15) T cells were analyzed as described above. (A) Absolute numbers of CD4+ and CD8+ donor T cells were enumerated following T cell transfer with WT (black symbols) or STAT1 Tg (red symbols) cells. (B) Expression of CD44 and CD62L on CD4+ and CD8+ donor T cells was assessed by flow cytometry in LNs. The percentages and absolute cell counts of CD4+ and CD8+ donor T cell subsets in RAG–/– mice transferred with WT (black symbols) or STAT1 Tg (red symbols) T cells are presented. (C) LN cells were stimulated ex vivo with PMA/ionomycin. IFN-γ production by donor T cells was assessed by intracellular staining, and plots represent CFSE fluorescence versus IFN-γ on gated CD45.2+ CD3+ CD4+ and CD8+ lymphocytes. The percentages of IFN-γ–producing donor T cells are indicated. Background in nonstimulated controls was < 1%. A nonparametric Mann-Whitney test was performed for comparisons between groups. Data are from 5 independent experiments out of 5, including an average of 3–4 mice per group per experiment and presented as box and whisker plots showing the median value bounded by the first and third quartiles in the box, with whiskers extending to the minimum and maximum values.