posted on 2020-04-14, 22:44authored byAda AdminAda Admin, David Arribas-Layton, Perrin Guyer, Thomas Delong, Mylinh Dang, I-Ting Chow, Cate Speake, Carla J. Greenbaum, William W. Kwok, Rocky L. Baker, Kathryn Haskins, Eddie A. James
cells isolated from the pancreatic infiltrates of non-obese diabetic mice have
been shown to recognize epitopes formed by the covalent cross-linking of
proinsulin and secretory granule peptides.
Formation of such hybrid insulin peptides (HIPs) was confirmed through
mass spectrometry and responses to HIPs were observed among the islet-infiltrating
T cells of pancreatic organ donors and in the peripheral blood of individuals
with type 1 diabetes (T1D). However, questions
remain about the prevalence of HIP-specific T cells in humans, the sequences
they recognize, and their role in disease.
We identified six novel HIPs that are recognized in the context of
DRB1*04:01, discovered by utilizing a library of theoretical HIP sequences
derived from insulin fragments covalently linked to one another or to fragments
of secretory granule proteins or other islet-derived proteins. We demonstrate that T cells that recognize
these HIPs are detectable in the peripheral blood of subjects with T1D and
exhibit an effector memory phenotype. HIP-reactive
T cell clones produced Th1-associated cytokines and proliferated in response to
human islet preparations. These results
support the relevance of HIPs in human disease, further establishing a novel
post-translational modification that may contribute to the loss of peripheral
tolerance in T1D.
This work was supported by the National Institutes of Health (NIH) grant R01-DK-081166 (K.H.), R21AI133059 (R.L.B.), Juvenile Diabetes Research Foundation grant 2-SRA-2018-551-S-B (E.A.J), and the American Diabetes Association Pathway to stop Diabetes 1-15-ACE-14 (T.D.).