title: Recent thymic emigrants are the preferential precursors of regulatory T cells differentiated in the periphery.
abstract: Most Forkhead box P3(+) (Foxp3(+)) CD4 regulatory T cell (Treg) precursors are newly formed thymocytes that acquire Foxp3 expression on antigen encounter in the thymus. Differentiation of Treg, however, can also occur in the periphery. What limits this second layer of self- and nonself-reactive Treg production in physiological conditions remains to be understood. In this work, we tested the hypothesis that, similarly to thymic Treg, the precursors of peripheral Treg are immature T cells. We show that CD4(+)CD8(-)Foxp3(-) thymocytes and recent thymic emigrants (RTEs), contrarily to peripheral naïve mature cells, efficiently differentiate into Treg on transfer into lymphopenic mice. By varying donor and recipient mice and conducting ex vivo assays, we document that the preferential conversion of newly formed T cells does not require intrathymic preactivation, is cell-intrinsic, and correlates with low and high sensitivity to natural inhibitors and inducers of Foxp3 expression, such as IL-6, T-cell receptor triggering, and TGF-β. Finally, ex vivo analysis of human thymocytes and peripheral blood T cells revealed that human RTE and newly developed T cells share an increased potential to acquire a FOXP3(bright)CD25(high) Treg phenotype. Our findings indicating that RTEs are the precursors of Tregs differentiated in the periphery should guide the design of Treg-based therapies.
authors.affiliation: Instituto Gulbenkian de Ciência, 2780-901 Oeiras, Portugal.
authors.forename: Ricardo S
authors.initials: RS
authors.lastname: Paiva
authors.forename: Andreia C
authors.initials: AC
authors.lastname: Lino
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Bergman
authors.forename: Iris
authors.initials: I
authors.lastname: Caramalho
authors.forename: Ana E
authors.initials: AE
authors.lastname: Sousa
authors.forename: Santiago
authors.initials: S
authors.lastname: Zelenay
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Demengeot
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D060168:Thymocytes / Q000166:cytology* / Q000276:immunology / Q000637:transplantation; D016212:Transforming Growth Factor beta / Q000276:immunology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015850:Interleukin-6; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta