Autoimmunity against a defective ribosomal insulin gene product in type 1 diabetes

Abstract

Identification of epitopes that are recognized by diabetogenic T cells and cause selective beta cell destruction in type 1 diabetes (T1D) has focused on peptides originating from native beta cell proteins. Translational errors represent a major potential source of antigenic peptides to which central immune tolerance is lacking1,2. Here, we describe an alternative open reading frame within human insulin mRNA encoding a highly immunogenic polypeptide that is targeted by T cells in T1D patients. We show that cytotoxic T cells directed against the N-terminal peptide of this nonconventional product are present in the circulation of individuals diagnosed with T1D, and we provide direct evidence that such CD8+ T cells are capable of killing human beta cells and thereby may be diabetogenic. This study reveals a new source of nonconventional polypeptides that act as self-epitopes in clinical autoimmune disease.

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Figure 1: Schematic representation of open reading frames (ORFs) found in the human insulin mRNA.
Figure 2: The human insulin mRNA harbors an alternative open reading frame.
Figure 3: Immunogenicity of insulin-derived, nonconventional polypeptide.
Figure 4: INS-DRIP1–9-specific CTLs kill human beta cells in vitro.

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Acknowledgements

We thank H.-J. Aanstoot (Diabeter), L. Mearin (Department of Pediatrics, LUMC), L. Wicker and J. Todd (Cambridge University, UK) for providing patient blood samples; M. Peakman (King's College, London, UK) for kindly sharing the PPI-specific CD8+ T cell clone; S.J. Cramer, M.J.W.E. Rabelink, T.J.M. Pool, K. Franken and A.H. de Ru for expert technical support; and J.R.F. Abreu for qDot analysis. This work is supported by the Dutch Diabetes Research Foundation, the DON Foundation and the Juvenile Diabetes Research foundation.

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Contributions

B.O.R., R.C.H. and A.Z. conceived and directed the project and wrote the manuscript. M.J.L.K. performed the key experiments and analyzed the data. P.A.v.V. performed mass spectrometry experiments. A.M.J. and S.L. cloned DRiP1–9-specific CTLs. M.v.L., T.N. and A.R.v.d.S. selected patient samples, performed ELISPOT assay and characterized CD8+ clones. F.C. and E.J.P.d.K. provided human islets.

Corresponding author

Correspondence to Bart O Roep.

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Competing interests

Leiden University Medical Center has filed international patent applications (EP16152400.4 and EP16154295.6) related to the insulin DRiP polypeptide (inventors B.O.R. and A.Z.).

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Kracht, M., van Lummel, M., Nikolic, T. et al. Autoimmunity against a defective ribosomal insulin gene product in type 1 diabetes. Nat Med 23, 501–507 (2017). https://doi.org/10.1038/nm.4289

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