title: CD4(+) T cell anergy prevents autoimmunity and generates regulatory T cell precursors.
abstract: The role of anergy, an acquired state of T cell functional unresponsiveness, in natural peripheral tolerance remains unclear. In this study, we found that anergy was selectively induced in fetal antigen-specific maternal CD4(+) T cells during pregnancy. A naturally occurring subpopulation of anergic polyclonal CD4(+) T cells, enriched for self antigen-specific T cell antigen receptors, was also present in healthy hosts. Neuropilin-1 expression in anergic conventional CD4(+) T cells was associated with hypomethylation of genes related to thymic regulatory T cells (Treg cells), and this correlated with their ability to differentiate into Foxp3(+) Treg cells that suppressed immunopathology. Thus, our data suggest that not only is anergy induction important in preventing autoimmunity but also it generates the precursors for peripheral Treg cell differentiation.
authors.affiliation: Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.|The Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Lokesh A
authors.initials: LA
authors.lastname: Kalekar
authors.affiliation: Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.|The Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Shirdi E
authors.initials: SE
authors.lastname: Schmiel
authors.affiliation: Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.|The Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Sarada L
authors.initials: SL
authors.lastname: Nandiwada
authors.affiliation: Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.|The Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Wing Y
authors.initials: WY
authors.lastname: Lam
authors.affiliation: Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.|The Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Laura O
authors.initials: LO
authors.lastname: Barsness
authors.affiliation: Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.|The Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
authors.affiliation: The Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.|Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Gretta L
authors.initials: GL
authors.lastname: Stritesky
authors.affiliation: The Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.|Department of Microbiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Deepali
authors.identifier: http://orcid.org/0000-0002-8215-7639
authors.initials: D
authors.lastname: Malhotra
authors.affiliation: Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.|The Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Pauken
authors.affiliation: The Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.|Department of Microbiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Linehan
authors.affiliation: The Comparative Pathology Core at the Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: M Gerard
authors.initials: MG
authors.lastname: O'Sullivan
authors.affiliation: Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.|The Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Fife
authors.affiliation: The Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.|Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Hogquist
authors.affiliation: The Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.|Department of Microbiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Marc K
authors.identifier: http://orcid.org/0000-0001-8009-7655
authors.initials: MK
authors.lastname: Jenkins
authors.affiliation: Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.|The Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Mueller
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D017635:Clonal Anergy / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology; D019673:Genes, T-Cell Receptor alpha; D054502:Histocompatibility, Maternal-Fetal / Q000276:immunology*; D015151:Immunoblotting; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D039942:Neuropilin-1 / Q000378:metabolism; D061166:Peripheral Tolerance / Q000276:immunology*; D054504:Precursor Cells, T-Lymphoid / Q000276:immunology*; D011247:Pregnancy; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017634:Self Tolerance; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D060168:Thymocytes / Q000276:immunology
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell; D039942:Neuropilin-1
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