title: IL-7R signaling in regulatory T cells maintains peripheral and allograft tolerance in mice.
abstract: Foxp3(+)CD4(+) regulatory T cells (Treg) have a crucial role in controlling CD4(+) T-cell activation, proliferation, and effector function. However, the molecular mechanisms regulating Treg function remain poorly understood. Here we assessed the role of IL-7, a key cytokine regulating T-cell homeostasis, in suppressor capacity of Treg. Using a skin allograft model in which transplant acceptance is controlled by the number of transferred Treg, we find that Treg impair the proliferation of allogeneic CD4(+) T cells, decrease production of IFNγ by effector T cells, and prevent early and increase late IL-7 induction by lymph node stromal cells. Increased IL-7 availability enhanced Treg survival, stabilized Treg molecular signature, enhanced surface IL-2Rα expression, and improved IL-2 binding of Treg, which diminished proliferation of alloreactive CD4(+) T cells. Sequestration of IL-7 or impairment of IL-7R signaling after allograft transplantation abolished Treg-mediated tolerance by limiting their suppressive capacity. Aged Il7rα-ΔTreg mice displayed mild symptoms of autoimmunity correlating with impaired expansion of effector Treg in response to IL-2. Thus, IL-7R signaling on Treg supports the functional activity of effector Treg by increasing their IL-2 sensitivity in the lymph node during peripheral and allograft tolerance.
authors.affiliation: Department of Biomedicine, Immunoregulation, University of Basel and University Hospital of Basel, Basel 4031, Switzerland; m.schmaler@unibas.ch simona.rossi@unibas.ch.
authors.forename: Mathias
authors.initials: M
authors.lastname: Schmaler
authors.affiliation: Department of Biomedicine, Immunoregulation, University of Basel and University Hospital of Basel, Basel 4031, Switzerland;
authors.forename: Maria A S
authors.initials: MA
authors.lastname: Broggi
authors.affiliation: Department of Biomedicine, Immunoregulation, University of Basel and University Hospital of Basel, Basel 4031, Switzerland;
authors.forename: Nadège
authors.initials: N
authors.lastname: Lagarde
authors.affiliation: Department of Biomedicine, Immunoregulation, University of Basel and University Hospital of Basel, Basel 4031, Switzerland;
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Stöcklin
authors.affiliation: Department of Biomedicine, Transplantation Immunology and Nephrology, University of Basel and University Hospital of Basel, Basel 4031, Switzerland;
authors.forename: Carolyn G
authors.initials: CG
authors.lastname: King
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital of Basel, Basel 4058, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Finke
authors.affiliation: Department of Biomedicine, Immunoregulation, University of Basel and University Hospital of Basel, Basel 4031, Switzerland; m.schmaler@unibas.ch simona.rossi@unibas.ch.
authors.forename: Simona W
authors.initials: SW
authors.lastname: Rossi
mesh_terms: D000818:Animals; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D006652:Histological Techniques; D007376:Interleukin-2 / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D061166:Peripheral Tolerance / Q000276:immunology*; D020395:Receptors, Interleukin-7 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D016038:Skin Transplantation; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: D017931:DNA Primers; D007376:Interleukin-2; D020395:Receptors, Interleukin-7
keywords: IL-2; IL-7; IL-7R; regulatory T cell; skin transplantation