{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T02:45:30Z","timestamp":1789785930589,"version":"4.0.1"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2006,7,1]],"date-time":"2006-07-01T00:00:00Z","timestamp":1151712000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u2212\/\u2212) 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\u2212\/\u2212 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 (CD3\u03b5\u2212\/\u2212) 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.<\/jats:p>","DOI":"10.4049\/jimmunol.177.1.53","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T19:47:14Z","timestamp":1397850434000},"page":"53-60","source":"Crossref","is-referenced-by-count":34,"title":["Tolerance to Proinsulin-2 Is Due to Radioresistant Thymic Cells"],"prefix":"10.1093","volume":"177","author":[{"given":"Be\u0301atrice","family":"Faideau","sequence":"first","affiliation":[{"name":"Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale (INSERM), Unite\u0301 561, Groupe Hospitalier Cochin-Saint Vincent de Paul , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"Lotton","sequence":"additional","affiliation":[{"name":"Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale (INSERM), Unite\u0301 561, Groupe Hospitalier Cochin-Saint Vincent de Paul , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Lucas","sequence":"additional","affiliation":[{"name":"Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale (INSERM), Unite\u0301 561, Groupe Hospitalier Cochin-Saint Vincent de Paul , Paris ,","place":["France"]},{"name":"Department of Immunology, Cochin Institute, INSERM, Unite\u0301 567, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, Rene\u0301 Descartes University, Cochin Hospital , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Tardivel","sequence":"additional","affiliation":[{"name":"Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale (INSERM), Unite\u0301 561, Groupe Hospitalier Cochin-Saint Vincent de Paul , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F","family":"Elliott","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Alberta , Edmonton ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Boitard","sequence":"additional","affiliation":[{"name":"Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale (INSERM), Unite\u0301 561, Groupe Hospitalier Cochin-Saint Vincent de Paul , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Claude","family":"Carel","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, Groupe Hospitalier Cochin-Saint Vincent de Paul, Universite\u0301 Paris V , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2006,7,1]]},"reference":[{"key":"2026020210142394600_R1","first-page":"668","volume-title":"Curr. 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