Individual nonobese diabetic mice exhibit unique patterns of CD8+ T cell reactivity to three islet antigens, including the newly identified widely expressed dystrophia myotonica kinase.

Document Type

Article

Publication Date

2004

Keywords

Autoantigens, CD8-Positive-T-Lymphocytes, Cells-Cultured, Clone-Cells, Female, Glucose-6-Phosphatase, H-2-Antigens, Insulin, Islets-of-Langerhans, Lymphocyte-Activation, Mice-Inbred-NOD, Mice-Transgenic, Molecular-Mimicry, Peptides, Protein-Binding, Protein-Serine-Threonine-Kinases, Proteins, Receptors-Antigen-T-Cell

First Page

6727

Last Page

6734

JAX Source

J Immunol 2004 Dec; 173(11):6727-34.

Abstract

Spontaneous autoimmune diabetes development in NOD mice requires both CD8(+) and CD4(+) T cells. Three pathogenic CD8(+) T cell populations (represented by the G9C8, 8.3, and AI4 clones) have been described. Although the Ags for G9C8 and 8.3 are known to be insulin and islet-specific glucose-6-phosphatase catalytic subunit-related protein, respectively, only mimotope peptides had previously been identified for AI4. In this study, we used peptide/MHC tetramers to detect and quantify these three pathogenic populations among beta cell-reactive T cells cultured from islets of individual NOD mice. Even within age-matched groups, each individual mouse exhibited a unique distribution of beta cell-reactive CD8(+) T cells, both in terms of the number of tetramer-staining populations and the relative proportion of each population in the islet infiltrate. Thus, the inflammatory process in each individual follows its own distinctive course. Screening of a combinatorial peptide library in positional scanning format led to the identification of a peptide derived from dystrophia myotonica kinase (DMK) that is recognized by AI4-like T cells. Importantly, the antigenic peptide is naturally processed and presented by DMK-transfected cells. DMK is a widely expressed protein that is nonetheless the target of a beta cell-specific autoimmune response.

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