title: CD4+CD25+ regulatory T cell repertoire formation shaped by differential presentation of peptides from a self-antigen.
abstract: We have used TCR transgenic mice directed to different MHC class II-restricted determinants from the influenza virus hemagglutinin (HA) to analyze how specificity for self-peptides can shape CD4+CD25+ regulatory T (Treg) cell formation. We show that substantial increases in the number of CD4+CD25+ Treg cells can occur when an autoreactive TCR directed to a major I-E(d)-restricted determinant from HA develops in mice expressing HA as a self-Ag, and that the efficiency of this process is largely unaffected by the ability to coexpress additional TCR alpha-chains. This increased formation of CD4+CD25+ Treg cells in the presence of the self-peptide argues against models that postulate selective survival rather than induced formation as mechanisms of CD4+CD25+ Treg cell formation. In contrast, T cells bearing a TCR directed to a major I-A(d)-restricted determinant from HA underwent little or no selection to become CD4+CD25+ Treg cells in mice expressing HA as a self-Ag, correlating with inefficient processing and presentation of the peptide from the neo-self-HA polypeptide. These findings show that interactions with a self-peptide can induce thymocytes to differentiate along a pathway to become CD4+CD25+ Treg cells, and that peptide editing by DM molecules may help bias the CD4+CD25+ Treg cell repertoire away from self-peptides that associate weakly with MHC class II molecules.
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Larkin
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Rankin
authors.forename: Cristina Cozzo
authors.initials: CC
authors.lastname: Picca
authors.forename: Michael P
authors.initials: MP
authors.lastname: Riley
authors.forename: Scott A
authors.initials: SA
authors.lastname: Jenks
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Sant
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Caton
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D001324:Autoantigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D006389:Hemagglutinins, Viral / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009980:Influenza A virus / Q000276:immunology; D007739:L Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology* / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
chemical_list: D001324:Autoantigens; D006389:Hemagglutinins, Viral; D010455:Peptides; D011948:Receptors, Antigen, T-Cell