Cellular requirements for diabetes induction in DO11.10xRIPmOVA mice.
Type 1 diabetes (T1D) results from the immune-mediated destruction of the insulin-producing β-islet cells in the pancreas. The genetic and environmental mechanisms promoting the development of this disease remain poorly understood. We have explored the cellular requirements for T1D development in DO11.10xRIPmOVA (DORmO) mice, which carry a TCR transgene specific for an MHC class II-restricted epitope from OVA and express membrane-bound OVA in the pancreas under the control of the rat insulin promoter. We found that DORmO.RAG2(-/-) mice do not develop insulitis and are completely protected from diabetes, demonstrating that endogenous lymphocyte receptor rearrangement is required for disease development. Diabetes in DORmO mice is preceded by the development of OVA-specific autoantibodies and is delayed in B cell-deficient DORmO.JhD(-/-) mice, demonstrating that B cells contribute to disease progression. In addition, transfer of CD8(+) T cells from diabetic animals into DORmO.RAG2(-/-) mice promoted insulitis by OVA-specific CD4(+) T cells. Finally, although diabetes develops in DORmO mice in the presence of a significant population of Foxp3(+) OVA-specific regulatory T cells, boosting regulatory T cell numbers by injecting IL-2 immune complexes dampens autoantibody production and prevents development of insulitis and overt diabetes. These results help define the events leading to diabetes in DORmO mice and provide new insights into the cellular interactions required for disease development in an Ag-specific model of T1D.
Wesley
Johnna D
JD
Immunology Program, Benaroya Research Institute, Seattle, WA 98101, USA.
Sather
Blythe D
BD
Perdue
Nikole R
NR
Ziegler
Steven F
SF
Campbell
Daniel J
DJ
D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D007150:Immunohistochemistry; D007328:Insulin / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D011401:Promoter Regions, Genetic; D051381:Rats; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology
D000949:Histocompatibility Antigens Class II; D007328:Insulin; D010047:Ovalbumin