Pancreatic lymph node-derived CD4(+)CD25(+) Treg cells: highly potent regulators of diabetes that require TRANCE-RANK signals.
Inflammation can activate self-reactive CD8(+) T cells and induce autoimmunity. Here we show in a CD8(+) T cell-mediated model of type 1 diabetes that CD4(+)CD25(+) Treg cells prevent beta cell destruction following localized inflammation in the islets of Langerhans. These Treg cells accumulate preferentially in the pancreatic lymph nodes and islets but not other lymph nodes or spleen. PLN-derived Treg cells are extremely potent; only 2 x 10(3) cells are needed to prevent diabetes development, and their capacity to regulate is dependent on TNF-related activation induced cytokine-receptor activator of NFkappaB signals. Indeed, blockade of this pathway results in decreased frequency of CD4(+)CD25(+) Treg cells in the PLN, resulting in intra-islet differentiation of CD8(+) T cells into CTLs and rapid progression to diabetes.
Green
E Allison
EA
Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Choi
Yongwon
Y
Flavell
Richard A
RA
D000818:Animals; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology*; D002454:Cell Differentiation; D003921:Diabetes Mellitus, Experimental / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006023:Glycoproteins / Q000276:immunology*; D007515:Islets of Langerhans / Q000166:cytology / Q000276:immunology*; D008024:Ligands; D008198:Lymph Nodes / Q000166:cytology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053244:Osteoprotegerin; D010179:Pancreas / Q000166:cytology / Q000276:immunology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D015415:Biomarkers; D002352:Carrier Proteins; D006023:Glycoproteins; D008024:Ligands; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D015375:Receptors, Interleukin-2; D018124:Receptors, Tumor Necrosis Factor; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse