Novel model of double transgenic mouse results in autoimmune diabetes in males.
Identifying the type of diabetogenic CD8+T cells that initiate autoimmune diabetes (AID) is a critical step in designing appropriate strategies for the early detection of beta cell-directed autoimmunity and its progression to diabetes. We generated a novel double transgenic (Tg) mouse model on the naturally diabetes resistant C57Bl/6 background, co-expressing two transgenes including a specific TCR anti-lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) carried by CD8+T cells and LCMV-NP (as neo-self antigen) expressed by pancreatic beta cells. The resulting double Tg mouse showed partial thymic deletion of the NP-specific CD8+T cells. The escaping autoreactive NP-specific CD8+T cells joining the periphery were activated and gained effector functions. Both male and female mice mounted anti-NP antibodies, but only one-fourth adult males spontaneously developed AID. Significant upregulation of the CD44 and CD122 markers as compared to healthy male and female mice characterized the phenotype of diabetogenic CD8+T cells in diabetic male mice. We also show that only 10% of these CD8+T cells expressed programmed death 1 receptor (PD-1). Together, these results suggest that in our double Tg mouse model, Ag-specific effector CD44+CD122+PD-1-CD8+T cell subpopulation is associated with the pathogenesis of AID.
a Gastroenterology, Hepatology and Nutrition Division, CHU Sainte-Justine , Montreal , QC , Canada.|b Department of Microbiology , Infectiology and Immunology, University of Montreal , Montreal , QC , Canada.
Sylvie
S
Chabot
a Gastroenterology, Hepatology and Nutrition Division, CHU Sainte-Justine , Montreal , QC , Canada.|b Department of Microbiology , Infectiology and Immunology, University of Montreal , Montreal , QC , Canada.|c Department of Pediatrics , University of Montreal , Montreal , QC , Canada , and.
Fernando
F
Alvarez
d Immunology Division, Department of Pediatrics, University of Sherbrooke , Sherbrooke , QC , Canada.
Abdelaziz
A
Amrani
a Gastroenterology, Hepatology and Nutrition Division, CHU Sainte-Justine , Montreal , QC , Canada.
Idriss
I
Djilali-Saiah
D000818:Animals; D015551:Autoimmunity; D015415:Biomarkers; D001786:Blood Glucose; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D012737:Sex Factors
D015415:Biomarkers; D001786:Blood Glucose; D011948:Receptors, Antigen, T-Cell
Autoimmune diabetes; diabetogenic CD8+ T cells; effector T cell; male autoimmune disorder; transgenic mouse model