title: c-Rel controls multiple discrete steps in the thymic development of Foxp3+ CD4 regulatory T cells.
abstract: The development of natural Foxp3(+) CD4 regulatory T cells (nTregs) proceeds via two steps that involve the initial antigen dependent generation of CD25(+)GITR(hi)Foxp3(-)CD4(+) nTreg precursors followed by the cytokine induction of Foxp3. Using mutant mouse models that lack c-Rel, the critical NF-κB transcription factor required for nTreg differentiation, we establish that c-Rel regulates both of these developmental steps. c-Rel controls the generation of nTreg precursors via a haplo-insufficient mechanism, indicating that this step is highly sensitive to c-Rel levels. However, maintenance of c-Rel in an inactive state in nTreg precursors demonstrates that it is not required for a constitutive function in these cells. While the subsequent IL-2 induction of Foxp3 in nTreg precursors requires c-Rel, this developmental transition does not coincide with the nuclear expression of c-Rel. Collectively, our results support a model of nTreg differentiation in which c-Rel generates a permissive state for foxp3 transcription during the development of nTreg precursors that influences the subsequent IL-2 dependent induction of Foxp3 without a need for c-Rel reactivation.
authors: Centre for Immunology, Burnet Institute, Melbourne, Australia.
authors: George
authors: G
authors: Grigoriadis
authors: Ajithkumar
authors: A
authors: Vasanthakumar
authors: Ashish
authors: A
authors: Banerjee
authors: Raelene
authors: R
authors: Grumont
authors: Sarah
authors: S
authors: Overall
authors: Paul
authors: P
authors: Gleeson
authors: Frances
authors: F
authors: Shannon
authors: Steve
authors: S
authors: Gerondakis
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D057895:Haploinsufficiency / Q000187:drug effects; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000254:growth & development* / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D019409:Interleukin-15; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D020569:Proto-Oncogene Proteins c-rel; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor