title: Human naïve regulatory T-cells feature high steady-state turnover and are maintained by IL-7.
abstract: Naïve FoxP3-expressing regulatory T-cells (Tregs) are essential to control immune responses via continuous replenishment of the activated-Treg pool with thymus-committed suppressor cells. The mechanisms underlying naïve-Treg maintenance throughout life in face of the age-associated thymic involution remain unclear. We found that in adults thymectomized early in infancy the naïve-Treg pool is remarkably well preserved, in contrast to conventional naïve CD4 T-cells. Naïve-Tregs featured high levels of cycling and pro-survival markers, even in healthy individuals, and contrasted with other circulating naïve/memory CD4 T-cell subsets in terms of their strong γc-cytokine-dependent signaling, particularly in response to IL-7. Accordingly, ex-vivo stimulation of naïve-Tregs with IL-7 induced robust cytokine-dependent signaling, Bcl-2 expression, and phosphatidylinositol 3-kinase (PI3K)-dependent proliferation, whilst preserving naïve phenotype and suppressive capacity. Altogether, our data strongly implicate IL-7 in the thymus-independent long-term survival of functional naïve-Tregs, and highlight the potential of targeting the IL-7 pathway to modulate Tregs in different clinical settings.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.|Clínica Universitária de Imunoalergologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal.
authors.forename: Susana L
authors.initials: SL
authors.lastname: Silva
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Albuquerque
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Serra-Caetano
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Russell B
authors.initials: RB
authors.lastname: Foxall
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Pires
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Matoso
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.|Clínica Universitária de Medicina II, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal.
authors.forename: Susana M
authors.initials: SM
authors.lastname: Fernandes
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Ferreira
authors.affiliation: Infection, Immunity and Inflammation Department, Institut Cochin, INSERM U1016-CNRS UMR8104-Université Paris Descartes, Paris, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Cheynier
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.|Clínica Universitária de Medicina II, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal.
authors.forename: Rui M M
authors.initials: RM
authors.lastname: Victorino
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Iris
authors.initials: I
authors.lastname: Caramalho
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: João T
authors.initials: JT
authors.lastname: Barata
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Ana E
authors.initials: AE
authors.lastname: Sousa
mesh_terms: D000293:Adolescent; D000328:Adult; D002470:Cell Survival / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D015851:Interleukin-7 / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology*; D055815:Young Adult
chemical_list: D051858:Forkhead Transcription Factors; C508605:IL7 protein, human; D015851:Interleukin-7
keywords: IL-7; Immune response; Immunity; Immunology and Microbiology Section; human regulatory T-cells; naïve regulatory T-cells; regulatory T-cell homeostasis; thymectomy