title: CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion.
abstract: CD4+CD25+ T regulatory cells (Tregs) prevent autoimmune disease, yet little is known about precisely where they exert their influence naturally in a spontaneous autoimmune disorder. Here, we report that Tregs and T effector cells (Teffs) coexist within the pancreatic lesion before type 1 diabetes onset. We find that BDC2.5 T cell receptor transgenic animals contain a small subset of FoxP3 positive CD4+CD25+CD69- cells in the pancreas, actively turning over, expressing the clonotypic receptor, and containing functional regulatory activity. Gene expression profiling confirms that the CD4+CD25+CD69- cells in pancreatic tissue express transcripts diagnostic of regulatory cells, but with significantly higher levels of interleukin 10 and inducible costimulator (ICOS) than their lymph node counterparts. Blockade of ICOS rapidly converts early insulitis to diabetes, which disrupts the balance of Teffs and Tregs and promotes a very broad shift in the expression of the T regulatory-specific profile. Thus, CD4+CD25+69- Tregs operate directly in the autoimmune lesion and are dependent on ICOS to keep it in a nondestructive state.
authors.affiliation: Section on Immunology and Immunogenetics, Joslin Diabetes Center, Boston, MA 02215, USA.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Herman
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis / Q000502:physiology*; D015704:CD4 Antigens / Q000032:analysis*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology*; D020869:Gene Expression Profiling; D053450:Glucocorticoid-Induced TNFR-Related Protein; D060889:Inducible T-Cell Co-Stimulator Protein; D016753:Interleukin-10 / Q000502:physiology; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000473:pathology; D015375:Receptors, Interleukin-2 / Q000032:analysis*; D017475:Receptors, Nerve Growth Factor / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D053450:Glucocorticoid-Induced TNFR-Related Protein; D060889:Inducible T-Cell Co-Stimulator Protein; D016753:Interleukin-10; D037181:Lectins, C-Type; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D000099192:CD69 Antigens; C556694:Icos protein, mouse; C106544:Tnfrsf18 protein, mouse