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

Thomas Delong1,*, Timothy A. Wiles1, Rocky L. Baker1, Brenda Bradley1, Gene Barbour1, Richard Reisdorph2, Michael Armstrong2, Roger L. Powell2, Nichole Reisdorph2, Nitesh Kumar3, Colleen M. Elso3, Megan DeNicola4, Rita Bottino5, Alvin C. Powers6,7, David M. Harlan4, Sally C. Kent4, Stuart I. Mannering3,8, Kathryn Haskins1,*

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. Autoreactive T cells targeting hybrid peptides may explain how immune tolerance is broken in T1D.