PMID- 29562882 OWN - NLM STAT- MEDLINE DCOM- 20190708 LR - 20190708 IS - 1471-2172 (Electronic) IS - 1471-2172 (Linking) VI - 19 IP - 1 DP - 2018 Mar 21 TI - Low HLA binding of diabetes-associated CD8+ T-cell epitopes is increased by post translational modifications. PG - 12 LID - 10.1186/s12865-018-0250-3 [doi] LID - 12 AB - BACKGROUND: Type 1 diabetes (T1D) is thought to be an autoimmune disease driven by anti-islet antigen responses and mediated by T-cells. Recent published data suggests that T-cell reactivity to modified peptides, effectively neoantigens, may promote T1D. These findings have given more credence to the concept that T1D may not be solely an error of immune recognition but may be propagated by errors in protein processing or in modifications to endogenous peptides occurring as result of hyperglycemia, endoplasmic reticulum (ER) stress, or general beta cell dysfunction. In the current study, we hypothesized that diabetes-associated epitopes bound human leukocyte antigen (HLA) class I poorly and that post-translational modifications (PTM) to key sequences within the insulin-B chain enhanced peptide binding to HLA class I, conferring the CD8+ T-cell reactivity associated with T1D. RESULTS: We first identified, through the Immune Epitope Database (IEDB; www.iedb.org ), 138 published HLA class I-restricted diabetes-associated epitopes reported to elicit positive T-cell responses in humans. The peptide binding affinity for their respective restricting allele(s) was evaluated in vitro. Overall, 75% of the epitopes bound with a half maximal inhibitory concentration (IC50) of 8250 nM or better, establishing a reference affinity threshold for HLA class I-restricted diabetes epitopes. These studies demonstrated that epitopes from diabetes-associated antigens bound HLA with a lower affinity than those of microbial origin (binding threshold of 500 nM for 85% of the epitopes). Further predictions suggested that diabetes epitopes also bind HLA class I with lower affinity than epitopes associated with other autoimmune diseases. Therefore, we measured the effect of common PTM (citrullination, chlorination, deamidation, and oxidation) on HLA-A*02:01 binding of insulin-B-derived peptides, compared to native peptides. We found that these modifications increased binding for 44% of the insulin-B epitopes, but only 15% of the control peptides. CONCLUSIONS: These results demonstrate that insulin-derived epitopes, commonly associated with T1D, generally bind HLA class I poorly, but can be subject to PTM that improve their binding capacity and may, in part, be responsible for T-cell activation in T1D and subsequent beta cell death. FAU - Sidney, John AU - Sidney J AUID- ORCID: 0000-0002-0987-405X AD - La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92130, USA. jsidney@lji.org. FAU - Vela, Jose Luis AU - Vela JL AD - Novo Nordisk Research Center Seattle, Inc., 530 Fairview Ave N, Seattle, WA, 98109, USA. FAU - Friedrich, Dave AU - Friedrich D AD - Novo Nordisk Research Center Seattle, Inc., 530 Fairview Ave N, Seattle, WA, 98109, USA. FAU - Kolla, Ravi AU - Kolla R AD - La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92130, USA. FAU - von Herrath, Matthias AU - von Herrath M AD - Novo Nordisk Research Center Seattle, Inc., 530 Fairview Ave N, Seattle, WA, 98109, USA. FAU - Wesley, Johnna D AU - Wesley JD AD - Novo Nordisk Research Center Seattle, Inc., 530 Fairview Ave N, Seattle, WA, 98109, USA. FAU - Sette, Alessandro AU - Sette A AD - La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92130, USA. LA - eng PT - Journal Article DEP - 20180321 PL - England TA - BMC Immunol JT - BMC immunology JID - 100966980 RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (HLA Antigens) RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Insulin) RN - 0 (Peptides) SB - IM MH - Amino Acid Sequence MH - CD8-Positive T-Lymphocytes/*immunology/metabolism MH - Diabetes Mellitus, Type 1/*immunology/metabolism MH - Epitopes, T-Lymphocyte/*immunology/metabolism MH - HLA Antigens/*immunology/metabolism MH - Histocompatibility Antigens Class I/*immunology/metabolism MH - Humans MH - Insulin/immunology/metabolism MH - Peptides/immunology/metabolism MH - Protein Binding MH - *Protein Processing, Post-Translational PMC - PMC5863483 OTO - NOTNLM OT - Class I MHC OT - Diabetes OT - HLA-peptide binding affinity OT - Insulin OT - T cell epitopes COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not applicable. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: Matthias von Herrath is a member of the editorial board (Associate Editor) of BMC Immunology. Otherwise, all authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/03/23 06:00 MHDA- 2019/07/10 06:00 PMCR- 2018/03/21 CRDT- 2018/03/23 06:00 PHST- 2018/01/18 00:00 [received] PHST- 2018/03/14 00:00 [accepted] PHST- 2018/03/23 06:00 [entrez] PHST- 2018/03/23 06:00 [pubmed] PHST- 2019/07/10 06:00 [medline] PHST- 2018/03/21 00:00 [pmc-release] AID - 10.1186/s12865-018-0250-3 [pii] AID - 250 [pii] AID - 10.1186/s12865-018-0250-3 [doi] PST - epublish SO - BMC Immunol. 2018 Mar 21;19(1):12. doi: 10.1186/s12865-018-0250-3.