Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide.
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.
Martinez
Nathan R
NR
Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Augstein
Petra
P
Moustakas
Antonis K
AK
Papadopoulos
George K
GK
Gregori
Silvia
S
Adorini
Luciano
L
Jackson
David C
DC
Harrison
Leonard C
LC
D000281:Administration, Intranasal; D019264:Adoptive Transfer; D000818:Animals; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D000939:Epitopes; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008958:Models, Molecular; D010455:Peptides / Q000008:administration & dosage / Q000627:therapeutic use*; D011384:Proinsulin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000502:physiology
D000939:Epitopes; D010455:Peptides; D011384:Proinsulin