title: Affinity-based selection of regulatory T cells occurs independent of agonist-mediated induction of Foxp3 expression.
abstract: Natural regulatory T (nT(reg)) cells recognize self-peptides with high affinity, yet the understanding of how affinity influences their selection in the thymus is incomplete. We use altered peptide ligands in transgenic mice and in organ culture to create thymic environments spanning a broad range of ligand affinity. We demonstrate that the nT(reg) TCR repertoire is shaped by affinity-based selection, similar to conventional T cells. The effect of each ligand on the two populations is distinct, consistent with early nT(reg) cell lineage specification. Foxp3 expression is an independent process that does not rely on "high affinity" binding per se, but requires a high-potency agonistic interaction for its induction. The timing of ligand exposure, TGFbeta signaling, and the organization of the thymic architecture are also important. The development of nT(reg) cells is therefore a multistep process in which ligand affinity, potency, and timing of presentation all play a role in determining cell fate.
authors.affiliation: Section of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Lance M
authors.initials: LM
authors.lastname: Relland
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Mishra
authors.forename: Dipica
authors.initials: D
authors.lastname: Haribhai
authors.forename: Brandon
authors.initials: B
authors.lastname: Edwards
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ziegelbauer
authors.forename: Calvin B
authors.initials: CB
authors.lastname: Williams
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006454:Hemoglobins / Q000276:immunology; D007113:Immunity, Innate; D008024:Ligands; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000819:agonists* / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000819:agonists* / Q000378:metabolism / Q000502:physiology; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000196:embryology / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006454:Hemoglobins; D008024:Ligands; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; C079201:hemoglobin (64-76)