Journal article

Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion

Thomas Delong, Timothy A Wiles, Rocky L Baker, Brenda Bradley, Gene Barbour, Richard Reisdorph, Michael Armstrong, Roger L Powell, Nichole Reisdorph, Nitesh Kumar, Colleen M Elso, Megan DeNicola, Rita Bottino, Alvin C Powers, David M Harlan, Sally C Kent, Stuart I Mannering, Kathryn Haskins

SCIENCE | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2016

Abstract

T cell-mediated destruction of insulin-producing β cells in the pancreas causes type 1 diabetes (T1D). CD4 T cell responses play a central role in β cell destruction, but the identity of the epitopes recognized by pathogenic CD4 T cells remains unknown. We found that diabetes-inducing CD4 T cell clones isolated from nonobese diabetic mice recognize epitopes formed by covalent cross-linking of proinsulin peptides to other peptides present in β cell secretory granules. These hybrid insulin peptides (HIPs) are antigenic for CD4 T cells and can be detected by mass spectrometry in β cells. CD4 T cells from the residual pancreatic islets of two organ donors who had T1D also recognize HIPs. Autorea..

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Grants

Awarded by NIH


Awarded by American Diabetes Association


Awarded by Australian National Health and Medical Research Council (NHMRC)


Awarded by Juvenile Diabetes Research Foundation


Awarded by Helmsley Charitable Trust


Awarded by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES


Awarded by NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES


Awarded by Veterans Affairs


Funding Acknowledgements

The following funding sources supported this research: NIH grant 1K01DK094941 (T.D.); American Diabetes Association Pathway to Stop Diabetes Grant 1-15-ACE-14 (T.D.); American Diabetes Association grant 1-15-JF-04 (R.L.B.); NIH grant 1R01DK081166 (K.H.); the Australian National Health and Medical Research Council (NHMRC) APP1061961 (S.M.); Juvenile Diabetes Research Foundation, Career Development Award 5-CDA2014210-A-N (S.M.); Operational Infrastructure Support Program from the Victorian State Government of Australia (S.M.); Helmsley Charitable Trust 2015PG-T1D057 (S.C.K.); Juvenile Diabetes Research Foundation grant 2-SRA-2015-68-Q-R (A.C.P., D.M.H.); NIH grant 5U01DK89572 (A.C.P., D.M.H.); NIH grant DK104211 (A.C.P). We thank the NIH tetramer core for providing tetramer reagents. A patent application related to the work on the hybrid peptides has been filed (Colorado University Technology Transfer Office file no. CU3769H-PPA1, Compositions and methods for diagnosing autoimmune diseases; T.D. and K.H. as inventors). The data presented in this manuscript are tabulated in the main paper and in the supplementary materials section.