title: Tolerance to proinsulin-2 is due to radioresistant thymic cells.
abstract: Proinsulin is a key Ag in type 1 diabetes, but the mechanisms regulating proinsulin immune tolerance are unknown. We have shown that preproinsulin-2 gene-deficient mice (proins-2(-/-)) are intolerant to proinsulin-2. In this study, we analyzed the mechanisms underlying T cell-mediated tolerance to proinsulin-2 in 129/Sv nonautoimmune mice. The expression of one proinsulin-2 allele, whatever its parental origin, was sufficient to maintain tolerance. The site of proinsulin-2 expression relevant to tolerance was evaluated in thymus and bone marrow chimeras. CD4+ T cell reactivity to proinsulin-2 was independent of proinsulin-2 expression in radiation-sensitive bone marrow-derived cells. A wt thymus restored tolerance in proins-2(-/-) mice. Conversely, the absence of the preproinsulin-2 gene in radioresistant thymic cells was sufficient to break tolerance. Although chimeric animals had proinsulin-2-reactive CD4+ T cells in their peripheral repertoire, they displayed no insulitis or insulin Abs, suggesting additional protective mechanisms. In a model involving transfer to immunodeficient (CD3epsilon(-/-)) mice, naive and proinsulin-2-primed CD4+ T cells were not activated, but could be activated by immunization regardless of whether the recipient mice expressed proinsulin-2. Furthermore, we could not identify a role for putative specific T cells regulating proinsulin-2-reactive CD4+ T in transfer experiments. Thus, proinsulin-2 gene expression by radioresistant thymic epithelial cells is involved in the induction of self-tolerance, and additional factors are required to induce islet abnormalities.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 561, Groupe Hospitalier Cochin-Saint Vincent de Paul, 82 avenue Denfert Rochereau, 75014 Paris, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Faideau
authors.forename: Chantal
authors.initials: C
authors.lastname: Lotton
authors.forename: Bruno
authors.initials: B
authors.lastname: Lucas
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tardivel
authors.forename: John F
authors.initials: JF
authors.lastname: Elliott
authors.forename: Christian
authors.initials: C
authors.lastname: Boitard
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Carel
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000528:radiation effects / Q000637:transplantation; D049109:Cell Proliferation / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011384:Proinsulin / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D011828:Radiation Chimera; D017634:Self Tolerance / Q000528:radiation effects; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000528:radiation effects* / Q000637:transplantation
chemical_list: D007371:Interferon-gamma; D011384:Proinsulin