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Tracing the action of IL‐2 in tolerance to islet‐specific antigen
Author(s) -
Liston Adrian,
Siggs Owen M,
Goodnow Christopher C
Publication year - 2007
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1038/sj.icb.7100049
Subject(s) - islet , biology , avidity , clonal deletion , foxp3 , immunology , t cell receptor , microbiology and biotechnology , antigen , t cell , endocrinology , diabetes mellitus , immune system
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.