title: Mature mainstream TCR alpha beta+CD4+ thymocytes expressing L-selectin mediate "active tolerance" in the nonobese diabetic mouse.
abstract: Pathogenic autoreactive T lymphocytes are mediators of spontaneous insulin-dependent diabetes in nonobese diabetic (NOD) mice. This is demonstrated by their capacity to transfer diabetes into syngeneic immunoincompetent recipients. In addition, especially in prediabetic NOD mice, peripheral CD4+ T lymphocytes were identified that are highly effective, in conventional mixing cotransfer experiments, at preventing disease transfer. The present data demonstrate that mature heat-stable Ag-TCR alpha beta+CD8-thymocytes from prediabetic NOD mice also express this inhibitory capacity. Selection using an L-selectin (CD62L)-specific Ab showed that TCR alpha/beta+CD4+CD62L+ thymocytes, emerging from the mainstream differentiation pathway, concentrate this ability to regulate autoreactive effectors. Compared with mature TCR alpha beta+CD8- thymocytes, significantly lower numbers of TCR alpha beta+CD4+CD62L+ were sufficient to achieve an efficient inhibition of disease transfer into NOD-scid recipients. This protective ability was potentiated following in vitro culture in the presence of IL-7. In contrast, TCR alpha beta+CD62L- thymocytes, highly enriched in class I-restricted NK T cells, were unable to influence diabetes transfer. Identical results were obtained using thymocytes that have been cultured in vitro for 4 days in the presence of IL-7. These results support the active role in NOD mice of a thymus-derived CD4+ subset that controls peripheral pathogenic autoimmune effectors.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 25, Hôpital Necker, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Herbelin
authors.forename: J M
authors.initials: JM
authors.lastname: Gombert
authors.forename: F
authors.initials: F
authors.lastname: Lepault
authors.forename: J F
authors.initials: JF
authors.lastname: Bach
authors.forename: L
authors.initials: L
authors.lastname: Chatenoud
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D007108:Immune Tolerance; D007110:Immunity, Active; D015851:Interleukin-7 / Q000494:pharmacology; D019041:L-Selectin / Q000096:biosynthesis* / Q000502:physiology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000502:physiology*; D013154:Spleen / Q000637:transplantation; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation
chemical_list: D000276:Adjuvants, Immunologic; D015851:Interleukin-7; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019041:L-Selectin