Journal article
Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion
T Delong, TA Wiles, RL Baker, B Bradley, G Barbour, R Reisdorph, M Armstrong, RL Powell, N Reisdorph, N Kumar, CM Elso, M DeNicola, R Bottino, AC Powers, DM Harlan, SC Kent, SI Mannering, K Haskins
Science | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2016
Abstract
Tcell-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 Tcell 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. Autoreacti..
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Awarded by National Institutes of Health
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.