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CD4(+)CD25(+)Foxp3(+) natural regulatory T cells (T reg cells) maintain self-tolerance and suppress autoimmune diseases such as type 1 diabetes and inflammatory bowel disease (IBD). In addition to their effects on T cells, T reg cells are essential for maintaining normal numbers of dendritic cells (DCs): when T reg cells are depleted, there is a compensatory Flt3-dependent increase in DCs. However, little is known about how T reg cell homeostasis is maintained in vivo. We demonstrate the existence of a feedback regulatory loop between DCs and T reg cells. We find that loss of DCs leads to a loss of T reg cells, and that the remaining T reg cells exhibit decreased Foxp3 expression. The DC-dependent loss in T reg cells leads to an increase in the number of T cells producing inflammatory cytokines, such as interferon gamma and interleukin 17. Conversely, increasing the number of DCs leads to increased T reg cell division and accumulation by a mechanism that requires major histocompatibility complex II expression on DCs. The increase in T reg cells induced by DC expansion is sufficient to prevent type 1 autoimmune diabetes and IBD, which suggests that interference with this feedback loop will create new opportunities for immune-based therapies.

Original publication

DOI

10.1084/jem.20090746

Type

Journal article

Journal

The Journal of experimental medicine

Publication Date

10/08/2009

Volume

206

Pages

1853 - 1862

Addresses

Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA. gdarrasse@rockefeller.edu

Keywords

Dendritic Cells, Animals, Mice, Inbred NOD, Mice, Transgenic, Mice, Inflammatory Bowel Diseases, Diabetes Mellitus, Type 1, Antibodies, Monoclonal, Cytokines, Flow Cytometry, Regression Analysis, Cell Proliferation, Genes, MHC Class II, Homeostasis, Feedback, T-Lymphocytes, Regulatory, Forkhead Transcription Factors