title: Agonist ligands expressed by thymic epithelium enhance positive selection of regulatory T lymphocytes from precursors with a normally diverse TCR repertoire.
abstract: CD4+CD25+ regulatory T lymphocytes play a crucial role in inhibition of autoimmune pathology. In accordance with this physiological role, it is now well established that the repertoire of these lymphocytes is strongly enriched in autospecific cells. However, despite extensive investigation, the thymic mechanisms involved in development of regulatory T cells remain incompletely defined. To address the issue of selection of regulatory T cell precursors in mice with a naturally diverse TCR repertoire, we have analyzed development of superantigen-specific regulatory T cells in hemopoietic chimeras in which endogenous super-antigens are exclusively presented by thymic epithelial cells. Our results demonstrate that recognition of agonist ligands expressed by thymic epithelium does not lead to deletion but substantially enhances development of mature regulatory T cells. Interestingly, also development of a small subpopulation of CD25-expressing T cells lacking expression of the transcription factor Foxp3, thought to be autospecific, is enhanced by expression of the agonist ligand on thymic epithelium. Based on quantitative arguments, we propose that commitment to the regulatory T cell lineage is not dictated by the specificity of precursors, but that recognition of the agonist ligand expressed by thymic epithelium substantially enhances their positive selection.
authors.affiliation: Centre de Physiopathologie Toulouse Purpan, INSERM Unité 563, Paul Sabatier University, 31024 Toulouse Cedex 3, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Ribot
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 / Q000235:genetics; D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D011828:Radiation Chimera; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis* / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D018089:Superantigens / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D018984:Epitopes, T-Lymphocyte; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D018089:Superantigens