Altered connexin 43 expression underlies age-dependent decrease of regulatory T cell suppressor function in nonobese diabetic mice.
Type 1 diabetes is one of the most extensively studied autoimmune diseases, but the cellular and molecular mechanisms leading to T cell-mediated destruction of insulin-producing β cells are still not well understood. In this study, we show that regulatory T cells (T(regs)) in NOD mice undergo age-dependent loss of suppressor functions exacerbated by the decreased ability of activated effector T cells to upregulate Foxp3 and generate T(regs) in the peripheral organs. This age-dependent loss is associated with reduced intercellular communication mediated by gap junctions, which is caused by impaired upregulation and decreased expression of connexin 43. Regulatory functions can be corrected, even in T cells isolated from aged, diabetic mice, by a synergistic activity of retinoic acid, TGF-β, and IL-2, which enhance connexin 43 and Foxp3 expression in T(regs) and restore the ability of conventional CD4(+) T cells to upregulate Foxp3 and generate peripherally derived T(regs). Moreover, we demonstrate that suppression mediated by T(regs) from diabetic mice is enhanced by a novel reagent, which facilitates gap junction aggregation. In summary, our report identifies gap junction-mediated intercellular communication as an important component of the T(reg) suppression mechanism compromised in NOD mice and suggests how T(reg) mediated immune regulation can be improved.
Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, GA 30912;
Michal
M
Kuczma
Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, GA 30912; The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; and.
Cong-Yi
CY
Wang
Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, GA 30912;
Leszek
L
Ignatowicz
Virginia Tech Carilion Research Institute, Roanoke, VA 24015.
Robert
R
Gourdie
Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, GA 30912; pkraj@odu.edu.
Piotr
P
Kraj
D000367:Age Factors; D000818:Animals; D002450:Cell Communication / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D018031:Connexin 43 / Q000096:biosynthesis* / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D017629:Gap Junctions / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000276:immunology; D007376:Interleukin-2 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation
D018031:Connexin 43; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C543076:GJA1 protein, mouse; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D050799:STAT5 Transcription Factor; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D014212:Tretinoin