title: Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells.
abstract: Regulatory T cells (Treg cells) express members of the tumor-necrosis factor (TNF) receptor superfamily (TNFRSF), but the role of those receptors in the thymic development of Treg cells is undefined. We found here that Treg cell progenitors had high expression of the TNFRSF members GITR, OX40 and TNFR2. Expression of those receptors correlated directly with the signal strength of the T cell antigen receptor (TCR) and required the coreceptor CD28 and the kinase TAK1. The neutralization of ligands that are members of the TNF superfamily (TNFSF) diminished the development of Treg cells. Conversely, TNFRSF agonists enhanced the differentiation of Treg cell progenitors by augmenting responsiveness of the interleukin 2 receptor (IL-2R) and transcription factor STAT5. Costimulation with the ligand of GITR elicited dose-dependent enrichment for cells of lower TCR affinity in the Treg cell repertoire. In vivo, combined inhibition of GITR, OX40 and TNFR2 abrogated the development of Treg cells. Thus, expression of members of the TNFRSF on Treg cell progenitors translated strong TCR signals into molecular parameters that specifically promoted the development of Treg cells and shaped the Treg cell repertoire.
authors.affiliation: Center for Immunology, Masonic Cancer Center, and the Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Shawn A
authors.initials: SA
authors.lastname: Mahmud
authors.affiliation: Center for Immunology, Masonic Cancer Center, and the Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Luke S
authors.initials: LS
authors.lastname: Manlove
authors.affiliation: Center for Immunology, Masonic Cancer Center, and the Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Schmitz
authors.affiliation: Center for Immunology, Masonic Cancer Center, and the Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Immunology, Masonic Cancer Center, and the Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Owen
authors.affiliation: Department of Microbiology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Schenkel
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Boomer
authors.affiliation: 1] Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA. [2] Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Green
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
authors.affiliation: Center for Immunology, Masonic Cancer Center, and the Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Hogquist
authors.affiliation: Center for Immunology, Masonic Cancer Center, and the Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Farrar
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020239:Receptor Cross-Talk / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000819:agonists*; D053262:Receptors, OX40 / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D018106:CD28 Antigens; D053450:Glucocorticoid-Induced TNFR-Related Protein; D020930:MAP Kinase Kinase Kinases; D011948:Receptors, Antigen, T-Cell; D053262:Receptors, OX40; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D000099151:MAP Kinase Kinase Kinase 7; C106544:Tnfrsf18 protein, mouse; C505717:Tnfrsf4 protein, mouse