TY - JOUR
T1 - Differential impact of T cell repertoire diversity in diabetes-prone or -resistant IL-10 transgenic mice
AU - Balasa, Balaji
AU - Lee, Jae
AU - Sarvetnick, Nora
N1 - Funding Information:
1B.B. is successively supported by postdoctoral fellowships from the Juvenile Diabetes Foundation International (JDFI) and the Myasthenia Gravis Foundation of America, Inc. This work was supported by the Diabetes Interdisciplinary Research Program grant from JDFI and NIH Grant HD 29764 (N.S.). This is manuscript No. 11820-IMM. 2To whom correspondence should be addressed at Department of Immunology, The Scripps Research Institute, Mail Code IMM23, 10555 North Torrey Pines Road, La Jolla, CA 92037. Fax: 619-784-9083. E-mail: noras@scripps.edu.
PY - 1999/5/1
Y1 - 1999/5/1
N2 - Expression of IL-10 transgene (tg) in pancreatic β cells failed to induce autoimmune insulitis and diabetes in (BALB/c x NOD)F1 mice. However, IL-10-expressing tg littermates from backcrosses (N2 and N3) with NOD mice became diabetic at 5 to 10 weeks of age in an MHC-dependent manner. In this study, we tested the possibility that enhancement in frequency of islet antigen (Ag)-specific T cells overrides the protective effects of a diabetes- resistant genetic background and promotes diabetes in IL-10 tg (BALB/c x NOD)F1 mice. For this test, we introduced the IL-10 transgene into tg BDC2.5 mice expressing the islet Ag-specific Vβ4 T cell repertoire by breeding Ins- IL-10+/BALB/c mice with BDC2.5 mice. The progeny (Ins-IL-10+/BALB/c x BDC2.5+)F1 mice doubly tg for IL-10 and Vβ4 (BDC2.5) T cell repertoire, developed diabetes at 10 to 18 weeks of age with a much more aggressive T cell infiltrate in the pancreatic islets than in single tg mice. Surprisingly, these diabetic mice were free from acute pancreatitis but had apoptotic β cells in the islet infiltrate. Conversely, mice tg for Vβ4 (BDC2.5) T cell repertoire but not IL-10 had no diabetes and no apoptotic β cells in the islet infiltrate. Therefore, an increase in the frequency of islet-specific T cells apparently overcomes the protection from diabetes by a resistant genetic background. Interestingly, N2 backcross mice doubly tg for Vβ4 (BDC2.5) T cell repertoire and IL-10, compared to N2 backcross mice tg for IL-10 only, eventually became diabetic but with a delayed onset and reduced incidence of disease. These findings demonstrate that, along with IL- 10, an increase in frequency of islet antigen-specific T cells (a) overrides the protective effect of genetic resistance to autoimmune diabetes in F1 mice and (b) delays the onset of an otherwise accelerated diabetes in (Ins-IL- 10+/NOD)N2 backcross mice.
AB - Expression of IL-10 transgene (tg) in pancreatic β cells failed to induce autoimmune insulitis and diabetes in (BALB/c x NOD)F1 mice. However, IL-10-expressing tg littermates from backcrosses (N2 and N3) with NOD mice became diabetic at 5 to 10 weeks of age in an MHC-dependent manner. In this study, we tested the possibility that enhancement in frequency of islet antigen (Ag)-specific T cells overrides the protective effects of a diabetes- resistant genetic background and promotes diabetes in IL-10 tg (BALB/c x NOD)F1 mice. For this test, we introduced the IL-10 transgene into tg BDC2.5 mice expressing the islet Ag-specific Vβ4 T cell repertoire by breeding Ins- IL-10+/BALB/c mice with BDC2.5 mice. The progeny (Ins-IL-10+/BALB/c x BDC2.5+)F1 mice doubly tg for IL-10 and Vβ4 (BDC2.5) T cell repertoire, developed diabetes at 10 to 18 weeks of age with a much more aggressive T cell infiltrate in the pancreatic islets than in single tg mice. Surprisingly, these diabetic mice were free from acute pancreatitis but had apoptotic β cells in the islet infiltrate. Conversely, mice tg for Vβ4 (BDC2.5) T cell repertoire but not IL-10 had no diabetes and no apoptotic β cells in the islet infiltrate. Therefore, an increase in the frequency of islet-specific T cells apparently overcomes the protection from diabetes by a resistant genetic background. Interestingly, N2 backcross mice doubly tg for Vβ4 (BDC2.5) T cell repertoire and IL-10, compared to N2 backcross mice tg for IL-10 only, eventually became diabetic but with a delayed onset and reduced incidence of disease. These findings demonstrate that, along with IL- 10, an increase in frequency of islet antigen-specific T cells (a) overrides the protective effect of genetic resistance to autoimmune diabetes in F1 mice and (b) delays the onset of an otherwise accelerated diabetes in (Ins-IL- 10+/NOD)N2 backcross mice.
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U2 - 10.1006/cimm.1999.1484
DO - 10.1006/cimm.1999.1484
M3 - Article
C2 - 10222059
AN - SCOPUS:0032942742
VL - 193
SP - 170
EP - 178
JO - Cellular Immunology
JF - Cellular Immunology
SN - 0008-8749
IS - 2
ER -