title: Development of thymic Foxp3(+) regulatory T cells: TGF-β matters.
abstract: CD4(+) regulatory T cells expressing the transcription factor Foxp3 can be generated in the thymus (tTreg cells), but the cellular and molecular pathways driving their development remain incompletely understood. TGF-β is essential for the generation of Foxp3(+) Treg cells converted from peripheral naïve CD4(+) T cells (pTreg cells), yet a role for TGF-β in tTreg-cell development was initially refuted. Nevertheless, recent studies have unmasked a requirement for TGF-β in the generation of tTreg cells. Experimental evidence reveals that TGF-β in the context of TCR stimulation induces Foxp3 gene transcription in thymic Treg precursors, CD4(+) CD8(-) CD25(-) semimature and mature single-positive thymocytes. Intriguingly, thymic apoptosis was found to be intrinsically linked to the generation of tTreg cells, as apoptosis induced expression of TGF-β intrathymically. In this short review, we will highlight key data, discuss the experimental evidence and propose a modified model of tTreg-cell development involving TGF-β. We will also outline the remaining unresolved questions concerning generation of thymic Foxp3(+) Treg cells and provide our personal perspectives on the mechanisms controlling tTreg-cell development.
authors: Mucosal Immunology Section, OPCB, NIDCR, 30 Convent Dr., Bethesda, MD, USA.
authors: WanJun
authors: W
authors: Chen
authors: Joanne E
authors: JE
authors: Konkel
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D060168:Thymocytes / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta
keywords: Apoptosis; Foxp3; IL-2; TGF-β; Thymic Treg cells