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

作者：Scott M. Lieberman, Toshiyuki Takaki, Bingye Han, Pere Santamaría, DAVID V. SERREZE, Teresa P. DiLorenzo · 发表于：The Journal of Immunology · 年份：2004 · DOI：10.4049/jimmunol.173.11.6727 · 被引用次数：117 · 研究领域：Diabetes and associated disorders、T-cell and B-cell Immunology、Immune Cell Function and Interaction

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.