title: Impaired thymic expression of tissue-restricted antigens licenses the de novo generation of autoreactive CD4+ T cells in acute GVHD.
abstract: During acute graft-versus-host disease (aGVHD) in mice, autoreactive T cells can be generated de novo in the host thymus implying an impairment in self-tolerance induction. As a possible mechanism, we have previously reported that mature medullary thymic epithelial cells (mTEC(high)) expressing the autoimmune regulator are targets of donor T-cell alloimmunity during aGVHD. A decline in mTEC(high) cell pool size, which purges individual tissue-restricted peripheral self-antigens (TRA) from the total thymic ectopic TRA repertoire, weakens the platform for central tolerance induction. Here we provide evidence in a transgenic mouse system using ovalbumin (OVA) as a model surrogate TRA that the de novo production of OVA-specific CD4(+) T cells during acute GVHD is a direct consequence of impaired thymic ectopic OVA expression in mTEC(high) cells. Our data, therefore, indicate that a functional compromise of the medullary mTEC(high) compartment may link alloimmunity to the development of autoimmunity during chronic GVHD.
authors.affiliation: Department of Biomedicine, University of Basel and Basel University Children's Hospital, Basel, Switzerland;
authors.forename: Simone
authors.initials: S
authors.lastname: Dertschnig
authors.affiliation: Benaroya Research Institute, Virginia Mason Hospital, Seattle, Washington;
authors.forename: Mathias M
authors.initials: MM
authors.lastname: Hauri-Hohl
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland; and.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Vollmer
authors.affiliation: Department of Biomedicine, University of Basel and Basel University Children's Hospital, Basel, Switzerland; Department of Paediatrics and the Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Georg A
authors.initials: GA
authors.lastname: Holländer
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland; and.
authors.forename: Werner
authors.initials: W
authors.lastname: Krenger
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000032:analysis / Q000276:immunology; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D017634:Self Tolerance; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology*
chemical_list: D001324:Autoantigens; D010047:Ovalbumin