title: Early events in the thymus affect the balance of effector and regulatory T cells.
abstract: In cellular immunology the critical balance between effector and regulatory mechanisms is highlighted by serious immunopathologies attributable to mutations in Foxp3, a transcription factor required for a major subset of regulatory T (Tr) cells. Thus, many studies have focused on the developmental origin of Tr cells, with the prevailing view that they emerge in the thymus from late-stage T-cell progenitors whose T-cell receptors (TCRs) engage high affinity (agonist) ligands. This study questions the completeness of that interpretation. Here we show that without any obvious effect on TCR-mediated selection, the normal differentiation of mouse gammabeta T cells into potent cytolytic and interferon-gamma-secreting effector cells is switched towards an aggregate regulatory phenotype by limiting the capacity of CD4+CD8+ T-cell progenitors to influence in trans early gammabeta cell progenitors. Unexpectedly, we found that the propensity of early TCR-alphabeta+ progenitors to differentiate into Foxp3+ Tr cells is also regulated in trans by CD4+CD8+ T-cell progenitor cells, before agonist selection.
authors.affiliation: Peter Gorer Department of Immunobiology, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK. d.pennington@qmul.ac.uk
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Pennington
authors.forename: Bruno
authors.initials: B
authors.lastname: Silva-Santos
authors.forename: Tobias
authors.initials: T
authors.lastname: Silberzahn
authors.forename: Mónica
authors.initials: M
authors.lastname: Escórcio-Correia
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Woodward
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Roberts
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Smith
authors.forename: P Julian
authors.initials: PJ
authors.lastname: Dyson
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Hayday
mesh_terms: D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D013234:Stem Cells / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology*; D013997:Time Factors
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta