Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects
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 i...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 14; pp. 4429 - 4434 |
|---|---|
| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
07.04.2015
National Acad Sciences |
| Subjects | |
| Online Access | Get full text |
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| 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.
Significance Certain class II major histocompatibility alleles confer disease risk for type 1 diabetes (T1D). Insulin-specific and other autoantibodies often precede T1D development, but major efforts at disease prevention using insulin preparations (subcutaneous, oral, and intranasal) to induce tolerance have not been effective. Measuring insulin-specific T-cell responses from the peripheral blood has been a challenging feat but would allow for assessment of therapeutic response in these trials. In our study, we report CD4 T-cell responses to a mutated insulin B-chain peptide in new-onset and established T1D as well as control subjects dependent on HLA-DQ genotype. Our results have important implications for the application and monitoring of insulin-specific therapies to prevent diabetes onset. |
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| AbstractList | 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. 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. Significance Certain class II major histocompatibility alleles confer disease risk for type 1 diabetes (T1D). Insulin-specific and other autoantibodies often precede T1D development, but major efforts at disease prevention using insulin preparations (subcutaneous, oral, and intranasal) to induce tolerance have not been effective. Measuring insulin-specific T-cell responses from the peripheral blood has been a challenging feat but would allow for assessment of therapeutic response in these trials. In our study, we report CD4 T-cell responses to a mutated insulin B-chain peptide in new-onset and established T1D as well as control subjects dependent on HLA-DQ genotype. Our results have important implications for the application and monitoring of insulin-specific therapies to prevent diabetes onset. 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. 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..., in an unfavorable position or register. Because of the similarities between IA... 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-... 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. (ProQuest: ... denotes formulae/symbols omitted.) Certain class II major histocompatibility alleles confer disease risk for type 1 diabetes (T1D). Insulin-specific and other autoantibodies often precede T1D development, but major efforts at disease prevention using insulin preparations (subcutaneous, oral, and intranasal) to induce tolerance have not been effective. Measuring insulin-specific T-cell responses from the peripheral blood has been a challenging feat but would allow for assessment of therapeutic response in these trials. In our study, we report CD4 T-cell responses to a mutated insulin B-chain peptide in new-onset and established T1D as well as control subjects dependent on HLA-DQ genotype. Our results have important implications for the application and monitoring of insulin-specific therapies to prevent diabetes onset. 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. 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.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. 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, IAg7, in an unfavorable position or register. Because of the similarities between IAg7and 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. |
| Author | Snell-Bergeona, Janet K. Davidson, Howard W. Gottlieb, Peter Kappler, John W. Carol, Kiekhaefer Nakayama, Maki McDaniel, Kristen Rewers, Marian Yu, Liping Fitzgerald-Miller, Lisa Michels, Aaron |
| Author_xml | – sequence: 1 givenname: Maki surname: Nakayama fullname: Nakayama, Maki organization: Barbara Davis Center for Childhood Diabetes, and Program in Structural Biology and Biophysics,University of Colorado School of Medicine, Aurora, CO 80045 – sequence: 2 givenname: Kristen surname: McDaniel fullname: McDaniel, Kristen organization: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045 – sequence: 3 givenname: Lisa surname: Fitzgerald-Miller fullname: Fitzgerald-Miller, Lisa organization: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045 – sequence: 4 givenname: Kiekhaefer surname: Carol fullname: Carol, Kiekhaefer organization: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045 – sequence: 5 givenname: Janet K. surname: Snell-Bergeona fullname: Snell-Bergeona, Janet K. organization: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045 – sequence: 6 givenname: Howard W. surname: Davidson fullname: Davidson, Howard W. organization: Barbara Davis Center for Childhood Diabetes, and Program in Structural Biology and Biophysics,University of Colorado School of Medicine, Aurora, CO 80045 – sequence: 7 givenname: Marian surname: Rewers fullname: Rewers, Marian organization: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045 – sequence: 8 givenname: Liping surname: Yu fullname: Yu, Liping organization: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045 – sequence: 9 givenname: Peter surname: Gottlieb fullname: Gottlieb, Peter organization: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045 – sequence: 10 givenname: John W. surname: Kappler fullname: Kappler, John W. organization: Department of Immunology and Microbiology, Program in Structural Biology and Biophysics,University of Colorado School of Medicine, Aurora, CO 80045; Department of Biomedical Research, Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206 – sequence: 11 givenname: Aaron surname: Michels fullname: Michels, Aaron organization: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25831495$$D View this record in MEDLINE/PubMed |
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| Copyright | Volumes 1–89 and 106–112, copyright as a collective work only; author(s) retains copyright to individual articles Copyright National Academy of Sciences Apr 7, 2015 |
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| DocumentTitleAlternate | Insulin T-cell responses in health and T1D |
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| Issue | 14 |
| Keywords | CD4 T cells autoimmunity insulin self-tolerance diabetes |
| Language | English |
| License | Freely available online through the PNAS open access option. |
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| Notes | http://dx.doi.org/10.1073/pnas.1502967112 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 Contributed by John W. Kappler, February 13, 2015 (sent for review October 10, 2014; reviewed by Mark Peakman and Jay Skyler) Reviewers: M.P., King's College London; and J.S., University of Miami. Author contributions: M.N., P.G., J.W.K., and A.M. designed research; K.M., L.F.-M., C.K., and L.Y. performed research; M.N., J.K.S.-B., J.W.K., and A.M. analyzed data; and M.N., H.W.D., M.R., P.G., J.W.K., and A.M. wrote the paper. |
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| Snippet | 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... Certain class II major histocompatibility alleles confer disease risk for type 1 diabetes (T1D). Insulin-specific and other autoantibodies often precede T1D... |
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| SubjectTerms | Adolescent Adult alleles Amino Acid Sequence Animals autoantibodies Autoantibodies - metabolism Biological Sciences CD4-positive T-lymphocytes CD4-Positive T-Lymphocytes - metabolism Child Cytokines Cytokines - metabolism Diabetes Diabetes Mellitus, Type 1 - metabolism disease prevention Female Genotype HLA-DQ Antigens - genetics Humans Inflammation - metabolism Insulin Insulin - genetics Insulin - metabolism insulin-dependent diabetes mellitus Interferon-gamma - metabolism Interleukin-10 - metabolism Male Mice Mice, Inbred NOD Middle Aged Molecular Sequence Data monitoring Mutation Peptides Receptors, Antigen, T-Cell - metabolism risk Risk assessment Sequence Homology, Amino Acid T cell receptors Young Adult |
| Title | Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects |
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