skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: C-terminal modification of the insulin B:11–23 peptide creates superagonists in mouse and human type 1 diabetes

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
ORCiD logo [1];  [2];  [1];  [1];  [3];  [4];  [4];  [5];  [6];  [5]
  1. National Jewish Health, Denver, CO (United States)
  2. Univ. of Colorado, Aurora, CO (United States)
  3. Cornell Univ., Lemont, IL (United States); Northeastern Collaborative Access Team, Lemont, IL (United States)
  4. Benaroya Research Inst., Seattle, WA (United States)
  5. National Jewish Health, Denver, CO (United States); Univ. of Colorado School of Medicine, Aurora, CO (United States); Univ. of Colorado Denver, Aurora, CO (United States)
  6. National Jewish Health, Denver, CO (United States); Univ. of Colorado, Aurora, CO (United States); Univ. of Colorado School of Medicine, Aurora, CO (United States); Univ. of Colorado Denver, Aurora, CO (United States)
+ Show Author Affiliations

A polymorphism at β57 in some major histocompatibility complex class II (MHCII) alleles of rodents and humans is associated with a high risk for developing type 1 diabetes (T1D). However, a highly diabetogenic insulin B chain epitope within the B:9–23 peptide is presented poorly by these alleles to a variety of mouse and human CD4 T cells isolated from either nonobese diabetic (NOD) mice or humans with T1D. We have shown for both species that mutations at the C-terminal end of this epitope dramatically improve presentation to these T cells. Here we present the crystal structures of these mutated peptides bound to mouse IAg7and human HLA-DQ8 that show how the mutations function to improve T-cell activation. In both peptide binding grooves, the mutation of B:22R to E in the peptide changes a highly unfavorable side chain for the p9 pocket to an optimal one that is dependent on the β57 polymorphism, accounting for why these peptides bind much better to these MHCIIs. Furthermore, a second mutation of the adjacent B:21 (E to G) removes a side chain from the surface of the complex that is highly unfavorable for a subset of NOD mouse CD4 cells, thereby greatly enhancing their response to the complex. These results point out the similarities between the mouse and human responses to this B chain epitope in T1D and suggest there may be common posttranslational modifications at the C terminus of the peptide in vivo to create the pathogenic epitopes in both species.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institutes of Health (NIH); JDRF; University of Colorado CCTSI Grant; Boettcher Foundation
Grant/Contract Number:
5T32-AI-074491; ES-025797; AI-18785; DK-032083; AI-118688; 1-PNF-2015-126-A-R; KL2 TR001080; P41 GM103403; S10 RR029205
OSTI ID:
1430360
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, Issue 1; ISSN 0027-8424
Publisher:
National Academy of SciencesCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 23 works
Citation information provided by
Web of Science

References (41)

Detection of Antigen-Specific T Cells with Multivalent Soluble Class II MHC Covalent Peptide Complexes journal June 1998
Transpeptidation and reverse proteolysis and their consequences for immunity journal January 2009
Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice journal April 1995
Specificity and detection of insulin-reactive CD4+ T cells in type 1 diabetes in the nonobese diabetic (NOD) mouse journal September 2011
Structural evidence for a germline-encoded T cell receptor–major histocompatibility complex interaction 'codon' journal August 2007
The Insulin-Specific T Cells of Nonobese Diabetic Mice Recognize a Weak MHC-Binding Segment in More Than One Form journal May 2007
Register shifting of an insulin peptide–MHC complex allows diabetogenic T cells to escape thymic deletion journal November 2011
Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects journal March 2015
Structure of a human insulin peptide–HLA-DQ8 complex and susceptibility to type 1 diabetes journal June 2001
A large fraction of HLA class I ligands are proteasome-generated spliced peptides journal October 2016
Peptide and Major Histocompatibility Complex–Specific Breaking of Humoral Tolerance to Native Insulin With the B9-23 Peptide in Diabetes-Prone and Normal Mice journal June 2001
Intracellular degradation of insulin and crinophagy are maintained by nitric oxide and cyclo-oxygenase 2 activity in isolated pancreatic islets journal May 2006
Proinsulin misfolding and endoplasmic reticulum stress during the development and progression of diabetes☆ journal April 2015
T cell receptor restriction of diabetogenic autoimmune NOD T cells journal March 1997
N-terminal additions to the WE14 peptide of chromogranin A create strong autoantigen agonists in type 1 diabetes journal October 2015
Rat Models of Type 1 Diabetes: Genetics, Environment, and Autoimmunity journal January 2004
Molecular Targeting of Islet Autoantigens journal April 2010
Immune recognition of a human renal cancer antigen through post-translational protein splicing journal January 2004
Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis journal January 2010
Genetic prediction of autoimmunity: Initial oligogenic prediction of anti-islet autoimmunity amongst DR3/DR4–DQ8 relatives of patients with type 1A diabetes journal January 2005
Diabetogenic T cells recognize insulin bound to IAg7 in an unexpected, weakly binding register journal June 2010
Binding of a soluble alpha beta T-cell receptor to superantigen/major histocompatibility complex ligands. journal August 1994
Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk journal July 2015
Islet-Derived CD4 T Cells Targeting Proinsulin in Human Autoimmune Diabetes journal December 2016
Autoreactive T cells specific for insulin B:11-23 recognize a low-affinity peptide register in human subjects with autoimmune diabetes journal September 2014
Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion journal February 2016
Germline TRAV5D-4 T-Cell Receptor Sequence Targets a Primary Insulin Peptide of NOD Mice journal February 2012
Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study. journal November 1988
Analysis of the Spontaneous T Cell Response to Insulin in NOD Mice journal December 1994
CELL BIOLOGY: Cutting and Pasting Antigenic Peptides journal April 2004
Do MHCII-Presented Neoantigens Drive Type 1 Diabetes and Other Autoimmune Diseases? journal August 2012
A Structural Framework for Deciphering the Link Between I-Ag7 and Autoimmune Diabetes journal April 2000
Natural peptides selected by diabetogenic DQ8 and murine I-Ag7 molecules show common sequence specificity journal August 2005
Affinity maturation of human CD4 by yeast surface display and crystal structure of a CD4-HLA-DR1 complex journal September 2011
An Antigenic Peptide Produced by Peptide Splicing in the Proteasome journal April 2004
Celiac disease and transglutaminase 2: a model for posttranslational modification of antigens and HLA association in the pathogenesis of autoimmune disorders journal December 2011
T-cell receptor (TCR) interaction with peptides that mimic nickel offers insight into nickel contact allergy journal October 2012
Structural Basis of Peptide Binding and Presentation by the Type I Diabetes-Associated MHC Class II Molecule of NOD Mice journal June 2000
Genetics of Type 1A Diabetes journal April 2009
A Time-Resolved Fluorescence Immunoassay (DELFIA) Increases the Sensitivity of Antigen-Driven Cytokine Detection journal January 2003
A molecule's right to choose: how diabetogenic class II MHC products bind peptides journal August 2005

Cited By (4)

Antibodies to oxidized insulin improve prediction of type 1 diabetes in children with positive standard islet autoantibodies journal February 2019
Does Air Pollution Crowd Out Foreign Direct Investment Inflows? Evidence from a Quasi-natural Experiment in China journal March 2019
How C-terminal additions to insulin B-chain fragments create superagonists for T cells in mouse and human type 1 diabetes journal April 2019
Programmed Death-1 Restrains the Germinal Center in Type 1 Diabetes journal July 2019

Similar Records

How C-terminal additions to insulin B-chain fragments create superagonists for T cells in mouse and human type 1 diabetes
Journal Article · Fri Apr 05 00:00:00 EDT 2019 · Science Immunology · OSTI ID:1430360
+13 more
N-terminal additions to the WE14 peptide of chromogranin A create strong autoantigen agonists in type 1 diabetes
Journal Article · Fri Oct 09 00:00:00 EDT 2015 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:1430360
+4 more
Predominant Occupation of the Class I MHC Molecule H-2Kwm7 with a Single Self-peptide Suggests a Mechanism for its Diabetes-protective Effect
Journal Article · Fri Jan 01 00:00:00 EST 2010 · International Immunology · OSTI ID:1430360
+6 more

Related Subjects

60 APPLIED LIFE SCIENCES
autoimmunity
peptide presentation
self-tolerance
posttranslational modification