Feedback control of regulatory T cell homeostasis by dendritic cells in vivo.
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.
Darrasse-Jèze
Guillaume
G
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA. gdarrasse@rockefeller.edu
Deroubaix
Stephanie
S
Mouquet
Hugo
H
Victora
Gabriel D
GD
Eisenreich
Thomas
T
Yao
Kai-hui
KH
Masilamani
Revati F
RF
Dustin
Michael L
ML
Rudensky
Alexander
A
Liu
Kang
K
Nussenzweig
Michel C
MC
D000818:Animals; D000911:Antibodies, Monoclonal; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism; D005246:Feedback / Q000502:physiology*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005802:Genes, MHC Class II / Q000235:genetics; D006706:Homeostasis / Q000502:physiology*; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D012044:Regression Analysis; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000502:physiology*
D000911:Antibodies, Monoclonal; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse