Regulatory T cells enter the pancreas during suppression of type 1 diabetes and inhibit effector T cells and macrophages in a TGF-beta-dependent manner.
Treg can suppress autoimmune diseases such as type 1 diabetes, but their in vivo activity during suppression remains poorly characterized. In type 1 diabetes, Treg activity has been demonstrated in the pancreatic lymph node, but little has been studied in the pancreas, the site of autoimmune islet destruction. In this study we induced islet-specific Treg from the BDC-6.9 TCR transgenic mouse by activation of T cells in the presence of TGF-beta. These Treg can suppress spontaneous diabetes as well as transfer of diabetes into NOD.scid mice by diabetic NOD spleen cells or activated BDC-2.5 TCR transgenic Th1 effector T cells. In the latter transfer model, we observed infiltration of the pancreas by both effector T cells and Treg, suggesting that Treg are active in the inflammatory site and are not just restricted to the draining lymph node. Within the pancreas, we demonstrate that Treg transfer causes a reduction in the number of effector Th1 T cells and macrophages, and also inhibits effector T-cell cytokine and chemokine production. Although we found no role for TGF-beta in vitro, transfection of effector T cells with a dominant-negative TGF-beta receptor demonstrated that in vivo suppression of diabetes by TGF-beta-induced Treg is TGF-beta-dependent.
Tonkin
Daniel R
DR
Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA.
Haskins
Kathryn
K
D019264:Adoptive Transfer; D000818:Animals; D016207:Cytokines / Q000097:blood / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D010179:Pancreas / Q000276:immunology*; D018125:Receptors, Transforming Growth Factor beta / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology*
D016207:Cytokines; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta