title: T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development.
abstract: The transcription factor Foxp3 is essential for the development of regulatory T (Treg) cells, yet its expression is insufficient for establishing the Treg cell lineage. Here we showed that Treg cell development was achieved by the combination of two independent processes, i.e., the expression of Foxp3 and the establishment of Treg cell-specific CpG hypomethylation pattern. Both events were induced by T cell receptor stimulation. The Treg cell-type CpG hypomethylation began in the thymus and continued to proceed in the periphery and could be fully established without Foxp3. The hypomethylation was required for Foxp3(+) T cells to acquire Treg cell-type gene expression, lineage stability, and full suppressive activity. Thus, those T cells in which the two events have concurrently occurred are developmentally set into the Treg cell lineage. This model explains how Treg cell fate and plasticity is controlled and can be exploited to generate functionally stable Treg cells.
authors.affiliation: Department of Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Japan.
authors.forename: Naganari
authors.initials: N
authors.lastname: Ohkura
authors.forename: Masahide
authors.initials: M
authors.lastname: Hamaguchi
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Morikawa
authors.forename: Kyoko
authors.initials: K
authors.lastname: Sugimura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanaka
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Ito
authors.forename: Motonao
authors.initials: M
authors.lastname: Osaki
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Riu
authors.initials: R
authors.lastname: Yamashita
authors.forename: Naoko
authors.initials: N
authors.lastname: Nakano
authors.forename: Jochen
authors.initials: J
authors.lastname: Huehn
authors.forename: Hans Joerg
authors.initials: HJ
authors.lastname: Fehling
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Kenta
authors.initials: K
authors.lastname: Nakai
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression; D006657:Histones / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006657:Histones; D011948:Receptors, Antigen, T-Cell