title: In vivo maintenance of T-lymphocyte unresponsiveness induced by thymic medullary epithelium requires antigen presentation by radioresistant cells.
abstract: The T-cell repertoire developing in the thymus is rid of autospecific cells by the process of thymic negative selection. Recognition of major histocompatibility complex (MHC)/self-peptide complexes expressed by thymic antigen-presenting cells (APC) of bone marrow origin leads to induction of apoptotic death of autospecific thymocytes. Induction of tolerance to self-antigens not presented by thymic APC is mediated by medullary thymic epithelial cells (mTEC) which express a very wide range of proteins, e.g. inducible and tissue-specific proteins. The main type of tolerance induced by mTEC is non-deletional and the issue of how it is maintained outside the thymus is therefore of crucial interest. We have previously shown that the non-T-cell receptor (TCR) -transgenic T-cell repertoire developing in conditions in which tolerance to self-MHC/peptide ligands is exclusively induced by mTEC is tolerant to syngeneic targets in vivo but lyses such targets in vitro. Here we report that this non-deletional in vivo self-tolerance is not due to active tolerance assured by known naturally occurring regulatory or immune-modulating T lymphocytes. Importantly, we show that in vivo maintenance of this therefore probably anergic state requires continued interaction of autospecific T cells with self-MHC/peptide ligands expressed by radioresistant cells while APC are incapable of maintaining the tolerant state. Therefore, maintenance of non-deletional T-lymphocyte tolerance to the wide range of self-antigens expressed by mTEC depends on continued interaction with radioresistant cells that very probably express a much more limited repertoire of antigens. Our data may therefore have important consequences for tolerance to tissue-specific and inducible self-antigens.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Centre de Physiopathologie de Toulouse-Purpan, Institut Claude de Preval, Toulouse, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Hudrisier
authors.forename: Sonia
authors.initials: S
authors.lastname: Feau
authors.forename: Véronique
authors.initials: V
authors.lastname: Bonnet
authors.forename: Paola
authors.initials: P
authors.lastname: Romagnoli
authors.forename: Joost P M
authors.initials: JP
authors.lastname: Van Meerwijk
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004847:Epithelial Cells / Q000276:immunology; D006649:Histocompatibility Antigens / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D011836:Radiation Tolerance / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000032:analysis; D017634:Self Tolerance; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*
chemical_list: D006649:Histocompatibility Antigens; D015375:Receptors, Interleukin-2