title: Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects.
abstract: Certain class II MHC (MHCII) alleles in mice and humans confer risk for or protection from type 1 diabetes (T1D). Insulin is a major autoantigen in T1D, but how its peptides are presented to CD4 T cells by MHCII risk alleles has been controversial. In the mouse model of T1D, CD4 T cells respond to insulin B-chain peptide (B:9-23) mimotopes engineered to bind the mouse MHCII molecule, IA(g7), in an unfavorable position or register. Because of the similarities between IA(g7) and human HLA-DQ T1D risk alleles, we examined control and T1D subjects with these risk alleles for CD4 T-cell responses to the same natural B:9-23 peptide and mimotopes. A high proportion of new-onset T1D subjects mounted an inflammatory IFN-γ response much more frequently to one of the mimotope peptides than to the natural peptide. Surprisingly, the control subjects bearing an HLA-DQ risk allele also did. However, these control subjects, especially those with only one HLA-DQ risk allele, very frequently made an IL-10 response, a cytokine associated with regulatory T cells. T1D subjects with established disease also responded to the mimotope rather than the natural B:9-23 peptide in proliferation assays and the proliferating cells were highly enriched in certain T-cell receptor sequences. Our results suggest that the risk of T1D may be related to how an HLA-DQ genotype determines the balance of T-cell inflammatory vs. regulatory responses to insulin, having important implications for the use and monitoring of insulin-specific therapies to prevent diabetes onset.
authors.affiliation: Barbara Davis Center for Childhood Diabetes, Department of Immunology and Microbiology, and.
authors.forename: Maki
authors.initials: M
authors.lastname: Nakayama
authors.affiliation: Barbara Davis Center for Childhood Diabetes.
authors.forename: Kristen
authors.initials: K
authors.lastname: McDaniel
authors.affiliation: Barbara Davis Center for Childhood Diabetes.
authors.forename: Lisa
authors.initials: L
authors.lastname: Fitzgerald-Miller
authors.affiliation: Barbara Davis Center for Childhood Diabetes.
authors.forename: Carol
authors.initials: C
authors.lastname: Kiekhaefer
authors.affiliation: Barbara Davis Center for Childhood Diabetes.
authors.forename: Janet K
authors.initials: JK
authors.lastname: Snell-Bergeon
authors.affiliation: Barbara Davis Center for Childhood Diabetes, Department of Immunology and Microbiology, and.
authors.forename: Howard W
authors.initials: HW
authors.lastname: Davidson
authors.affiliation: Barbara Davis Center for Childhood Diabetes.
authors.forename: Marian
authors.initials: M
authors.lastname: Rewers
authors.affiliation: Barbara Davis Center for Childhood Diabetes.
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.affiliation: Barbara Davis Center for Childhood Diabetes.
authors.forename: Peter
authors.initials: P
authors.lastname: Gottlieb
authors.affiliation: Department of Immunology and Microbiology, and Department of Biomedical Research, Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206 Program in Structural Biology and Biophysics, University of Colorado School of Medicine, Aurora, CO 80045; and aaron.michels@ucdenver.edu kapplerj@njhealth.org.
authors.forename: John W
authors.initials: JW
authors.lastname: Kappler
authors.affiliation: Barbara Davis Center for Childhood Diabetes, aaron.michels@ucdenver.edu kapplerj@njhealth.org.
authors.forename: Aaron
authors.initials: A
authors.lastname: Michels
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002648:Child; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007328:Insulin / Q000235:genetics* / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D006683:HLA-DQ Antigens; D007328:Insulin; D011948:Receptors, Antigen, T-Cell; D016753:Interleukin-10; D007371:Interferon-gamma
keywords: CD4 T cells; autoimmunity; diabetes; insulin; self-tolerance
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