title: Tracing the action of IL-2 in tolerance to islet-specific antigen.
abstract: Genetic variants of interleukin 2 (IL-2) and its receptor are associated with murine and human susceptibility to Type 1 diabetes, yet the role of IL-2 in controlling pancreatic islet-reactive T cells is unknown. Here, we develop a model where IL-2 deficiency precipitates a breakdown of self-tolerance and progression to diabetes, and its action upon diabetogenic islet-specific CD4 T cells can be tracked. We find that IL-2 is not required for Aire-dependent thymic clonal deletion of high-avidity diabetogenic clones, but is essential for thymic formation of islet-specific Foxp3-expressing CD4 T cells. The absence of IL-2 results in the expansion of low-avidity Foxp3(-) islet-reactive CD4 T cells. The mechanism by which IL-2 prevents diabetes is therefore through the establishment of a repertoire of islet-reactive Foxp3(+) T cells within the thymus, and limitation of the peripheral activation of low-avidity islet-reactive T cells that normally escape thymic negative selection.
authors: Immunogenomics Laboratory, John Curtin School of Medical Research and The Australian Phenomics Facility, The Australian National University, Canberra 2601, Australia. liston@u.washington.edu
authors: Adrian
authors: A
authors: Liston
authors: Owen M
authors: OM
authors: Siggs
authors: Christopher C
authors: CC
authors: Goodnow
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000172:deficiency / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D013950:Thymus Gland / Q000276:immunology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2