title: Differential requirement for IL-2 and IL-15 during bifurcated development of thymic regulatory T cells.
abstract: The developmental pathways of regulatory T cells (T(reg)) generation in the thymus are not fully understood. In this study, we reconstituted thymic development of Zap70-deficient thymocytes with a tetracycline-inducible Zap70 transgene to allow temporal dissection of T(reg) development. We find that T(reg) develop with distinctive kinetics, first appearing by day 4 among CD4 single-positive (SP) thymocytes. Accepted models of CD25(+)Foxp3(+) T(reg) selection suggest development via CD25(+)Foxp3(-) CD4 SP precursors. In contrast, our kinetic analysis revealed the presence of abundant CD25(-)Foxp3(+) cells that are highly efficient at maturing to CD25(+)Foxp3(+) cells in response to IL-2. CD25(-)Foxp3(+) cells more closely resembled mature T(reg) both with respect to kinetics of development and avidity for self-peptide MHC. These population also exhibited distinct requirements for cytokines during their development. CD25(-)Foxp3(+) cells were IL-15 dependent, whereas generation of CD25(+)Foxp3(+) specifically required IL-2. Finally, we found that IL-2 and IL-15 arose from distinct sources in vivo. IL-15 was of stromal origin, whereas IL-2 was of exclusively from hemopoetic cells that depended on intact CD4 lineage development but not either Ag-experienced or NKT cells.
authors.affiliation: Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London, NW7 1AA, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Marshall
authors.affiliation: Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London, NW7 1AA, United Kingdom.
authors.forename: Charles
authors.initials: C
authors.lastname: Sinclair
authors.affiliation: Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London, NW7 1AA, United Kingdom.
authors.forename: Sim
authors.initials: S
authors.lastname: Tung
authors.affiliation: Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London, NW7 1AA, United Kingdom benedict.seddon@ucl.ac.uk.
authors.forename: Benedict
authors.initials: B
authors.lastname: Seddon
mesh_terms: D000818:Animals; D001773:Blood Cells / Q000378:metabolism*; D015704:CD4 Antigens / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors; D019409:Interleukin-15 / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017154:Stromal Cells / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D013950:Thymus Gland / Q000276:immunology; D018183:Transplantation Chimera; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D019409:Interleukin-15; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse