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Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library

Nature Medicine volume 5, pages 1026–1031 (1999)Cite this article

Abstract

Type 1 diabetes is an autoimmune disease in which the insulin-producing pancreatic β cells are destroyed at an early age by an immune process that involves both CD4 and CD8 T lymphocytes. The identification of autoantigens in diabetes is very important for the design of antigen-specific immunotherapy. By screening a pancreatic islet cDNA library, we have identified the autoantigen recognized by highly pathogenic CD8 T cells in the non-obese diabetic mouse, one of the best animal models for human diabetes. This is the first identification, to our knowledge, of a CD8 T-cell epitope in an autoimmune disease. The peptide recognized by the cells is in the same region of the insulin B chain as the epitope recognized by previously isolated pathogenic CD4 T cells. This has very important implications for the potential use of insulin in preventative therapy.

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Figure 1: Phenotypic and functional characteristics of the G9C8 CD8 T-cell clone.
Figure 2: Autoantigen identification using COS-Kd cells transfected with islet cDNA library.
Figure 3: Functional responses of G9C8 CD8 T-cell clone to peptides, and frequency of T cells recognizing G9 tetramer in pancreatic islets of NOD mice.

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Acknowledgements

We thank M. Altieri for islet isolation for preparation of the cDNA library and J. Rife and M. Tang for technical assistance. We also thank C. Viret, R. Medzhitov, P. Cresswell and R. Sherwin for discussions. DNA sequencing and peptide synthesis was done by the W.M. Keck Biotechnology facility of Yale University School of Medicine. This work was supported by Project 1 and the NOD and mutant mouse core B and islet isolation core C of NIH/JDFI diabetes program project grant DK-53015. F.S.W. and L.W. are recipients of JDFI Career Development Awards. J.K. was a recipient of a Howard Hughes post-doctoral fellowship and C.D. was supported by a Student Research Fellowship from the American Heart Association. C.A.J.,Jr. is an investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Sections of Immunobiology, Yale School of Medicine, New Haven, 06520-8011, 310 Cedar Street, Connecticut, USA

    F. Susan Wong, Jaana Karttunen, Caroline Dumont & Irene Visintin

  2. Endocrinology, Yale School of Medicine, New Haven, 06520-8011, 310 Cedar Street, Connecticut, USA

    Li Wen

  3. Infectious Diseases, New Haven, 06520-8011, 310 Cedar Street, Connecticut, USA

    Ingrid M. Pilip & Eric G. Pamer

  4. Howard Hughes Medical Institute, Yale School of Medicine, New Haven, 06520-8011, 310 Cedar Street, Connecticut, USA

    Charles A. Janeway Jr.

  5. Division of Immunology, Department of Molecular and Cell Biology, University of California, Berkeley, 94720, California, USA

    Nilabh Shastri

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Correspondence to F. Susan Wong.

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Wong, F., Karttunen, J., Dumont, C. et al. Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library. Nat Med 5, 1026–1031 (1999). https://doi.org/10.1038/12465

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