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.

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.

• Authors: Scott M Lieberman, Toshiyuki Takaki, Bingye Han, Pere Santamaria, David V Serreze, Teresa P DiLorenzo
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 173 Issue 11 Pg. 6727-34 (Dec 01 2004) ISSN: 0022-1767 [Print] United States
• PMID: 15557165 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Autoantigens
• DMPK protein, mouse
• H-2 Antigens
• Histocompatibility Antigen H-2D
• Insulin
• Peptides
• Proteins
• Receptors, Antigen, T-Cell
• Myotonin-Protein Kinase
• Protein Serine-Threonine Kinases
• Glucose-6-Phosphatase
• G6pc2 protein, mouse

Topics

• Animals
• Antigen Presentation (immunology)
• Autoantigens (immunology, metabolism)
• CD8-Positive T-Lymphocytes (cytology, immunology, metabolism)
• Cells, Cultured
• Clone Cells
• Female
• Glucose-6-Phosphatase (immunology, metabolism)
• H-2 Antigens (immunology, metabolism)
• Histocompatibility Antigen H-2D
• Insulin (immunology, metabolism)
• Islets of Langerhans (enzymology, immunology, metabolism)
• Lymphocyte Activation (immunology)
• Male
• Mice
• Mice, Inbred NOD
• Mice, Transgenic
• Molecular Mimicry (immunology)
• Myotonin-Protein Kinase
• Peptides (immunology, metabolism)
• Protein Binding (immunology)
• Protein Serine-Threonine Kinases (immunology)
• Proteins (immunology, metabolism)
• Receptors, Antigen, T-Cell (metabolism)