title: Nr4a receptors are essential for thymic regulatory T cell development and immune homeostasis.
abstract: Regulatory T cells (T(reg) cells) develop from progenitor thymocytes after the engagement of T cell antigen receptors (TCRs) with high-affinity ligands, but the underlying molecular mechanisms are still unclear. Here we show that the Nr4a nuclear receptors, which are encoded by immediate-early genes upregulated by TCR stimulation in thymocytes, have essential roles in T(reg) cell development. Mice that lacked all Nr4a factors could not produce T(reg) cells and died early owing to systemic autoimmunity. Nr4a receptors directly activated the promoter of the gene encoding the transcription factor Foxp3, and forced activation of Nr4a receptors bypassed low-strength TCR signaling to drive the T(reg) cell developmental program. Our results suggest that Nr4a receptors have key roles in determining CD4(+) T cell fates in the thymus and thus contribute to immune homeostasis.
authors: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
authors: Takashi
authors: T
authors: Sekiya
authors: Ikkou
authors: I
authors: Kashiwagi
authors: Rei
authors: R
authors: Yoshida
authors: Tomohiro
authors: T
authors: Fukaya
authors: Rimpei
authors: R
authors: Morita
authors: Akihiro
authors: A
authors: Kimura
authors: Hiroshi
authors: H
authors: Ichinose
authors: Daniel
authors: D
authors: Metzger
authors: Pierre
authors: P
authors: Chambon
authors: Akihiko
authors: A
authors: Yoshimura
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D017781:Genes, Immediate-Early; D006706:Homeostasis; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000502:physiology*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D060168:Thymocytes / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D009419:Nerve Tissue Proteins; C539818:Nr4a1 protein, mouse; C539883:Nr4a2 protein, mouse; C490411:Nr4a3 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone