title: IL-7 determines the homeostatic fitness of T cells by distinct mechanisms at different signalling thresholds in vivo.
abstract: The cytokine interleukin (IL)-7 is essential for Treg-cell homeostasis. It remains unclear, however, whether IL-7 regulates the homeostatic fitness of T cells quantitatively and, if so, by what mechanisms. We addressed this question by analysing T cells exposed to different levels of IL-7 signalling in vivo. Using TCR transgenic mice that conditionally express IL-7Rα, we show that T-cell longevity in the absence of survival cues is not a cell-intrinsic property but rather a dynamic process of which IL-7 signalling is a key regulator. Naïve T cells deficient in IL-7Rα expression underwent rapid cell death within hours of in vitro culture. In contrast, the same T cells from lymphopenic hosts, in which IL-7 is non-limiting, were able to survive in culture independently of growth factors for many days. Surprisingly, different levels of IL-7 signalling in vivo evoked distinct molecular mechanisms to regulate homeostatic fitness. When IL-7 was non-limiting, increased survival was associated with up-regulation of anti-apoptotic Bcl2 family members. In contrast, in T-cell replete conditions i.e. when IL-7 is limiting, we found evidence that IL-7 regulated T-cell fitness by distinct non-transcriptional mechanisms. Together, these data demonstrate a quantitative aspect to IL-7 signalling dependent on distinct molecular mechanisms.
authors.affiliation: Division of Immune Cell Biology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Pearson
authors.forename: Ana
authors.initials: A
authors.lastname: Silva
authors.forename: Manoj
authors.initials: M
authors.lastname: Saini
authors.forename: Benedict
authors.initials: B
authors.lastname: Seddon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D015851:Interleukin-7 / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015851:Interleukin-7; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain