HLA-DQβ57, anti-insulin T cells and insulin mimicry in autoimmune diabetes

Type 1 diabetes (T1D) is caused by a T-cell-mediated destruction of insulin-secreting pancreatic islet β cells. The T1D-predisposing human leukocyte antigen (HLA) class II molecule, DQ8, binds and presents insulin B chain peptides in the thymus producing autoreactive CD4+ T cells[1][1]–[12][2]. Here, we show that this process is driven by negatively-charged T cell receptor (TCR) complementarity-determining region 3β (CDR3β) sequences interacting with alanine at position 57 of the DQ8 β chain. Since T1D aetiology is linked to gut microbiota dysbiosis[13][3]–[18][4], we hypothesized that the commensal proteome contains mimics of the primary insulin B:9-23 epitope that control TCR selection and tolerance. We identified a large set of bacterial proteins with significant similarity to insulin B:9-25, particularly from the transketolase (TKT) superfamily. We isolated a CD4+ TCR with a negatively-charged CDR3β from the pancreas of a DQ8-positive patient that was cross-reactive with one of these TKT peptides and insulin B:9-23. The T1D-protective molecule, DQ6, with the negatively-charged aspartic acid (D) at DQβ57(12,19), showed strong TKT mimotope binding, supporting a role for TKT-specific regulatory T cells in resistance to T1D. We propose that in a DQ8+DQ6− child with a proinflammatory dysbiotic gut microbiota, cross-reactive TKT-insulin B chain peptide T effector cells escape from the thymus and initiate T1D. TKT is a strong candidate because it is highly upregulated during weaning, a key period in T1D aetiology, and hence a prominent target for an autoimmune-prone immune system. Inhibiting gut dysbiosis and improving immune tolerance to TKT and other mimotopes, especially before and during weaning, could be a route to primary prevention of T1D and other common diseases. ### Competing Interest Statement JAT is a member of a GSK Human Genetics Advisory Board ### Funding Statement This work has been supported by a JDRF (4-SRA-2017-473-A-N) and Wellcome (107212/A/15/Z) Strategic Award. D-GAP was a centre grant funded by the JDRF (1-2007-1803). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: DGAP: Diabetes, Genes, Autoimmunity and Prevention: London Hampstead Research Committee of the NHS Health Research Authority gave ethical approval for this work; ethics reference number 08/H0720/25. Samples were transferred to ethics 08/H0308/153 Investigating Genes and Phenotypes of Type 1 Diabetes (Cambridgeshire 2 Research Ethics Committee) upon closure of the DGAP study. DMech: Investigating underlying causal mechanisms in type 1 diabetes South Central Oxford A Research Ethics committee of the NHS Health Research Authority gave ethical approval for this work; ethics reference number 18/SC/0559. The Network for Pancreatic Organ donors with Diabetes (nPOD): studies involving human participants were reviewed and approved by the University of Florida Institutional Research Board (IRB201600029). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study will be available upon reasonable request to the authors. [1]: #ref-1 [2]: #ref-12 [3]: #ref-13 [4]: #ref-18