Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3

By Wanjun Chen, W. Jin, N. Hardegen, K. Lei, Li Li, N. Marinos, G. McGrady, S. Wahl. Journal of Experimental Medicine, 2003

5,128 citations recorded by the source corpus.

CD4+CD25+ regulatory T cells (Treg) are instrumental in the maintenance of immunological tolerance. One critical question is whether Treg can only be generated in the thymus or can differentiate from peripheral CD4+CD25− naive T cells. In this paper, we present novel evidence that conversion of naive peripheral CD4+CD25− T cells into anergic/suppressor cells that are CD25+, CD45RB−/low and intracellular CTLA-4+ can be achieved through costimulation with T cell receptors (TCRs) and transforming growth factor β (TGF-β). Although transcription factor Foxp3 has been shown recently to be associated with the development of Treg, the physiological inducers for Foxp3 gene expression remain a mystery. TGF-β induced Foxp3 gene expression in TCR-challenged CD4+CD25− naive T cells, which mediated their transition toward a regulatory T cell phenotype with potent immunosuppressive potential. These converted anergic/suppressor cells are not only unresponsive to TCR stimulation and produce neither T helper cell 1 nor T helper cell 2 cytokines but they also express TGF-β and inhibit normal T cell proliferation in vitro. More importantly, in an ovalbumin peptide TCR transgenic adoptive transfer model, TGF-β–converted transgenic CD4+CD25+ suppressor cells proliferated in response to immunization and inhibited antigen-specific naive CD4+ T cell expansion in vivo. Finally, in a murine asthma model, coadministration of these TGF-β–induced suppressor T cells prevented house dust mite–induced allergic pathogenesis in lungs.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/e9fa325e088c5a9ef7d8d1674cead50fb802728a

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Citations in the corpus

Natural and Induced CD4+CD25+ Cells Educate CD4+CD25− Cells to Develop Suppressive Activity: The Role of IL-2, TGF-β, and IL-101 (2004, background): “(20), who documented that this cytokine increased FoxP3 gene expression in activated mouse CD4 CD25 cells.”
The IL-23/Th17 axis in the immunopathogenesis of psoriasis. (2009, background): “This finding was initially surprising as TGF-b1 is known to induce the development of regulatory T cells with a potent suppressor function (Chen et al., 2003).”
TGF-beta: a master of all T cell trades. (2008, neutral): “In vitro activation of CD4+CD25− or CD4+Foxp3− T cells in the presence of TGF-β leads to their acquisition of T cell suppressive activity, which is associated with the induction of Foxp3 expression (Chen et al., 2003b; Fantini et al., 2004; Wan and Flavell, 2005; Zheng et al., 2002).”
Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. (2012, background): “, 2005) or in the presence of TGF-b in vitro (Chen et al., 2003).”
Mammalian Krüppel-Like Factors in Health and Diseases (2010, background): “The transcription factor Foxp3 regulates the Treg cell lineage (138), and TGF- converts CD4 CD25 naive T cells into Foxp3 CD4 CD25 Treg cells in vitro and maintains Treg cells in vivo (63, 129, 247).”
Dual Roles of Immune Cells and Their Factors in Cancer Development and Progression (2011, background): “In addition, TGFplays a central role in the generation and function of CD4+ CD25+ Tregs (27).”
CREB/ATF-dependent T cell receptor–induced FoxP3 gene expression: a role for DNA methylation (2007, background): “Both IL-2 and transforming growth factor (TGF)-β can induce the conversion of CD4+CD25– into CD4+CD25+ T cells with elevated FoxP3 expression in vitro (14), which is consistent with the presence of both IL-2 and TGF-β response elements in the Il2ra gene (15–17).”
Foxp3+CD25+CD4+ natural regulatory T cells in dominant self‐tolerance and autoimmune disease (2006, background): “This makes them distinct from other adaptive Tregs that differentiate from naı̈ve T cells following antigen exposure in the periphery, although some Tregs that are phenotypically and functionally similar to thymus-produced CD25CD4 natural Tregs may be able to differentiate in the periphery from naı̈”
Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. (2011, neutral): “Tregs can be induced from naive T cells upon exposure to TGF-b and are propagated by IL-2 (Chen et al., 2003; Davidson et al., 2007; Rajewsky and von Boehmer, 2008).”