Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide
AuthorMartinez, NR; Augstein, P; Moustakas, AK; Papadopoulos, GK; Gregori, S; Adorini, L; Jackson, DC; Harrison, LC
Source TitleJournal of Clinical Investigation
PublisherAMER SOC CLINICAL INVESTIGATION INC
University of Melbourne Author/sJackson, David
AffiliationMicrobiology And Immunology
Document TypeJournal Article
CitationsMartinez, N. R., Augstein, P., Moustakas, A. K., Papadopoulos, G. K., Gregori, S., Adorini, L., Jackson, D. C. & Harrison, L. C. (2003). Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide. JOURNAL OF CLINICAL INVESTIGATION, 111 (9), pp.1365-1371. https://doi.org/10.1172/JCI200317166.
Access StatusAccess this item via the Open Access location
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC154446
C1 - Journal Articles Refereed
Insulin is a major target of the autoimmune response associated with destruction of pancreatic beta cells in type 1 diabetes. A peptide that spans the junction of the insulin B chain and the connecting (C) peptide in proinsulin has been reported to stimulate T cells from humans at risk for type 1 diabetes and autoimmune diabetes-prone NOD mice. Here we show that proinsulin B24-C36 peptide binds to I-A(g7), the MHC class II molecule of the NOD mouse, and, after intranasal administration, induces regulatory CD4(+) T cells that, in the absence of CD8(+) T cells, block the adoptive transfer of diabetes. Curiously, however, intranasal B24-C36 did not inhibit development of spontaneous diabetes in treated mice. We then determined that B24-C36, and its core sequence B25-C34, bind to K(d), the NOD mouse MHC class I molecule, and elicit CD8(+) CTLs. When the CD8(+) T lymphocyte epitope was truncated at the C34 valine anchor residue for binding to K(d), the residual CD4(+) T cell epitope, B24-C32/33, significantly inhibited diabetes development after a single intranasal dose. This study identifies a novel CTL epitope in proinsulin and demonstrates that the therapeutic potential of a "tolerogenic" autoantigen peptide can be compromised by the presence of an integral CTL epitope.
KeywordsImmunology not elsewhere classified; Infectious Diseases
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