Adaptive islet-specific regulatory CD4 T cells control autoimmune diabetes and mediate the disappearance of pathogenic Th1 cells in vivo.
Adaptive regulatory T cells that develop from naive CD4 cells in response to exposure to Ag can act as immunotherapeutic agents to control immune responses. We show that effectors generated from murine islet-specific CD4 cells by TCR stimulation with IL-2 and TGF-beta1 have potent suppressive activity. They prevent spontaneous development of type 1 diabetes in NOD mice and inhibit development of pancreatic infiltrates and disease onset orchestrated by Th1 effectors. These regulatory T cells do not require innate CD25+ regulatory cells for generation or function, nor do they share some characteristics typically associated with them, including expression of CD25. However, the adaptive population does acquire the X-linked forkhead/winged helix transcription factor, FoxP3, which is associated with regulatory T cell function and maintains expression in vivo. One mechanism by which they may inhibit Th1 cells is via FasL-dependent cytotoxicity, which occurs in vitro. In vivo, they eliminate Th1 cells in lymphoid tissues, where Fas/FasL interactions potentially play a role because Th1 cells persist when this pathway is blocked. The results suggest that adaptive regulatory CD4 cells may control diabetes in part by impairing the survival of islet-specific Th1 cells, and thereby inhibiting the localization and response of autoaggressive T cells in the pancreatic islets.
Department of Immunology, Sidney Kimmel Cancer Center, San Diego, CA 92131, USA.
Sarah E
SE
Weber
Judith
J
Harbertson
Elana
E
Godebu
Guthrie A
GA
Mros
Ryan C
RC
Padrick
Bryan D
BD
Carson
Steven F
SF
Ziegler
Linda M
LM
Bradley
D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control; D053222:Fas Ligand Protein; D005260:Female; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D018417:Th1 Cells / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D048069:Tumor Necrosis Factors / Q000378:metabolism
D000941:Antigens; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007376:Interleukin-2; D008562:Membrane Glycoproteins; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D048069:Tumor Necrosis Factors