title: Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus.
abstract: In multicellular organisms, specialized functions are delegated to distinct cell types whose identity and functional integrity are maintained upon challenge. However, little is known about the mechanisms enabling lineage inheritance and their biological implications. Regulatory T (Treg) cells, which express the transcription factor Foxp3, suppress fatal autoimmunity throughout the lifespan of animals. Here, we show that a dedicated Foxp3 intronic element CNS2 maintains Treg cell lineage identity by acting as a sensor of the essential Treg cell growth factor IL-2 and its downstream target STAT5. CNS2 sustains Foxp3 expression during division of mature Treg cells when IL-2 is limiting and counteracts proinflammatory cytokine signaling that leads to the loss of Foxp3. CNS2-mediated stable inheritance of Foxp3 expression is critical for adequate suppression of diverse types of chronic inflammation by Treg cells and prevents their differentiation into inflammatory effector cells. The described mechanism may represent a general principle of the inheritance of differentiated cell states.
authors.affiliation: Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Arvey
authors.affiliation: Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Chinen
authors.affiliation: Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Joris
authors.initials: J
authors.lastname: van der Veeken
authors.affiliation: Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Georg
authors.initials: G
authors.lastname: Gasteiger
authors.affiliation: Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address: rudenska@mskcc.org.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
mesh_terms: D000818:Animals; D018899:CpG Islands; D019175:DNA Methylation; D051858:Forkhead Transcription Factors / Q000235:genetics*; D007249:Inflammation / Q000473:pathology*; D007376:Interleukin-2 / Q000378:metabolism; D007438:Introns; D051379:Mice; D050436:Regulatory Elements, Transcriptional; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D050799:STAT5 Transcription Factor