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.
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.
Lieberman
Scott M
SM
Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Takaki
Toshiyuki
T
Han
Bingye
B
Santamaria
Pere
P
Serreze
David V
DV
DiLorenzo
Teresa P
TP
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D002999:Clone Cells; D005260:Female; D005952:Glucose-6-Phosphatase / Q000276:immunology / Q000378:metabolism; D006183:H-2 Antigens / Q000276:immunology / Q000378:metabolism; D064532:Histocompatibility Antigen H-2D; D007328:Insulin / Q000276:immunology / Q000378:metabolism; D007515:Islets of Langerhans / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D018716:Molecular Mimicry / Q000276:immunology; D065636:Myotonin-Protein Kinase; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000276:immunology*; D011506:Proteins / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism
D001324:Autoantigens; C585516:DMPK protein, mouse; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D007328:Insulin; D010455:Peptides; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse