C-rel controls multiple discrete steps in the thymic development of Foxp3+ CD4 regulatory T cells

George Grigoriadis, Ajithkumar Vasanthakumar, Ashish Banerjee, Raelene Joy Grumont, Sarah Overall, Paul A Gleeson, M Shannon, Steven Gerondakis

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The development of natural Foxp3+ CD4 regulatory T cells (nTregs) proceeds via two steps that involve the initial antigen dependent generation of CD25+GITRhiFoxp3-CD4+ nTreg precursors followed by the cytokine induction of Foxp3. Using mutant mouse models that lack c-Rel, the critical NF-I?B 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. A? 2011 Grigoriadis et al.
Original languageEnglish
Article numbere26851
Number of pages10
JournalPLoS ONE
Volume6
Issue number10
DOIs
Publication statusPublished - 2011

Cite this

Grigoriadis, George ; Vasanthakumar, Ajithkumar ; Banerjee, Ashish ; Grumont, Raelene Joy ; Overall, Sarah ; Gleeson, Paul A ; Shannon, M ; Gerondakis, Steven. / C-rel controls multiple discrete steps in the thymic development of Foxp3+ CD4 regulatory T cells. In: PLoS ONE. 2011 ; Vol. 6, No. 10.
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abstract = "The development of natural Foxp3+ CD4 regulatory T cells (nTregs) proceeds via two steps that involve the initial antigen dependent generation of CD25+GITRhiFoxp3-CD4+ nTreg precursors followed by the cytokine induction of Foxp3. Using mutant mouse models that lack c-Rel, the critical NF-I?B 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. A? 2011 Grigoriadis et al.",
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C-rel controls multiple discrete steps in the thymic development of Foxp3+ CD4 regulatory T cells. / Grigoriadis, George; Vasanthakumar, Ajithkumar; Banerjee, Ashish; Grumont, Raelene Joy; Overall, Sarah; Gleeson, Paul A; Shannon, M; Gerondakis, Steven.

In: PLoS ONE, Vol. 6, No. 10, e26851, 2011.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Grigoriadis, George

AU - Vasanthakumar, Ajithkumar

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AU - Overall, Sarah

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AU - Shannon, M

AU - Gerondakis, Steven

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