Epitopes described in "Specificity and detection of insulin-reactive CD4+ T cells in type 1 diabetes in the nonobese diabetic (NOD) mouse."

Article Authors:Frances Crawford; Brian Stadinski; Niyun Jin; Aaron Michels; Maki Nakayama; Philip Pratt; Philippa Marrack; George Eisenbarth; John W Kappler
Article Title:Specificity and detection of insulin-reactive CD4+ T cells in type 1 diabetes in the nonobese diabetic (NOD) mouse.
Reference Detail
Reference ID:1022493
Abstract:In the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D), an insulin peptide (B:9-23) is a major target for pathogenic CD4(+) T cells. However, there is no consensus on the relative importance of the various positions or "registers" this peptide can take when bound in the groove of the NOD MHCII molecule, IA(g7). This has hindered structural studies and the tracking of the relevant T cells in vivo with fluorescent peptide-MHCII tetramers. Using mutated B:9-23 peptides and methods for trapping the peptide in particular registers, we show that most, if not all, NOD CD4(+) T cells react to B:9-23 bound in low-affinity register 3. However, these T cells can be divided into two types depending on whether their response is improved or inhibited by substituting a glycine for the B:21 glutamic acid at the p8 position of the peptide. On the basis of these findings, we constructed a set of fluorescent insulin-IA(g7) tetramers that bind to most insulin-specific T-cell clones tested. A mixture of these tetramers detected a high frequency of B:9-23-reactive CD4(+) T cells in the pancreases of prediabetic NOD mice. Our data are consistent with the idea that, within the pancreas, unique processing of insulin generates truncated peptides that lack or contain the B:21 glutamic acid. In the thymus, the absence of this type of processing combined with the low affinity of B:9-23 binding to IA(g7) in register 3 may explain the escape of insulin-specific CD4(+) T cells from the mechanisms that usually eliminate self-reactive T cells.
Affiliations:Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206, USA.
Reference Type:Literature
PubMed ID:21949373
Journal:Proc Natl Acad Sci U S A
Journal Volume:108
Article Pages:16729-34
Journal ISSN:0027-8424
Article Chemical List:Histocompatibility Antigens Class II;I-A g7 antigen;Insulin;Peptide Fragments;insulin B (9-23)
Article MeSH List:Amino Acid Sequence; Animals; Baculoviridae; CD4-Positive T-Lymphocytes(immunology); Diabetes Mellitus, Type 1(immunology); Electrophoresis, Polyacrylamide Gel; Flow Cytometry; Histocompatibility Antigens Class II(immunology; metabolism); Hybridomas(immunology); Insulin(genetics; immunology; metabolism); Mice; Mice, Inbred NOD; Molecular Sequence Data; Peptide Fragments(genetics; immunology; metabolism); Protein Binding; Thymus Gland(immunology)
Curation Last Updated:2015-07-30 20:41:00