title: TSCOT+ thymic epithelial cell-mediated sensitive CD4 tolerance by direct presentation.
abstract: Although much effort has been directed at dissecting the mechanisms of central tolerance, the role of thymic stromal cells remains elusive. In order to further characterize this event, we developed a mouse model restricting LacZ to thymic stromal cotransporter (TSCOT)-expressing thymic stromal cells (TDLacZ). The thymus of this mouse contains approximately 4,300 TSCOT+ cells, each expressing several thousand molecules of the LacZ antigen. TSCOT+ cells express the cortical marker CDR1, CD40, CD80, CD54, and major histocompatibility complex class II (MHCII). When examining endogenous responses directed against LacZ, we observed significant tolerance. This was evidenced in a diverse T cell repertoire as measured by both a CD4 T cell proliferation assay and an antigen-specific antibody isotype analysis. This tolerance process was at least partially independent of Autoimmune Regulatory Element gene expression. When TDLacZ mice were crossed to a novel CD4 T cell receptor (TCR) transgenic reactive against LacZ (BgII), there was a complete deletion of double-positive thymocytes. Fetal thymic reaggregate culture of CD45- and UEA-depleted thymic stromal cells from TDLacZ and sorted TCR-bearing thymocytes excluded the possibility of cross presentation by thymic dendritic cells and medullary epithelial cells for the deletion. Overall, these results demonstrate that the introduction of a neoantigen into TSCOT-expressing cells can efficiently establish complete tolerance and suggest a possible application for the deletion of antigen-specific T cells by antigen introduction into TSCOT+ cells.
authors.affiliation: Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America,
authors.forename: Sejin
authors.initials: S
authors.lastname: Ahn
authors.forename: Gwanghee
authors.initials: G
authors.lastname: Lee
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Yang
authors.forename: Deokjae
authors.initials: D
authors.lastname: Lee
authors.forename: Seunghyuk
authors.initials: S
authors.lastname: Lee
authors.forename: Hyo Sun
authors.initials: HS
authors.lastname: Shin
authors.forename: Min Cheol
authors.initials: MC
authors.lastname: Kim
authors.forename: Kee Nyung
authors.initials: KN
authors.lastname: Lee
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.forename: Marc R
authors.initials: MR
authors.lastname: Theoret
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Jenkinson
authors.forename: Graham
authors.initials: G
authors.lastname: Anderson
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Moon Gyo
authors.initials: MG
authors.lastname: Kim
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology*; D007108:Immune Tolerance; D007763:Lac Operon / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology; D027981:Symporters / Q000235:genetics / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology
chemical_list: D027981:Symporters; C498632:Tscot protein, mouse