Helios Deficiency Predisposes the Differentiation of CD4+Foxp3- T Cells into Peripherally Derived Regulatory T Cells
- PMID: 31167776
- PMCID: PMC6615958
- DOI: 10.4049/jimmunol.1900388
Helios Deficiency Predisposes the Differentiation of CD4+Foxp3- T Cells into Peripherally Derived Regulatory T Cells
Abstract
The transcription factor Helios is expressed in a large percentage of Foxp3+ regulatory T (Treg) cells and is required for the maintenance of their suppressive phenotype, as mice with a selective deficiency of Helios in Treg cells spontaneously develop autoimmunity. However, mice with a deficiency of Helios in all T cells do not exhibit autoimmunity, despite the defect in the suppressor function of their Treg cell population, suggesting that Helios also functions in non-Treg cells. Although Helios is expressed in a small subset of CD4+Foxp3- and CD8+ T cells and its expression is upregulated upon T cell activation, its function in non-Treg cells remains unknown. To examine the function of Helios in CD4+Foxp3- T cells, we transferred Helios-sufficient or -deficient naive CD4+Foxp3- TCR transgenic T cells to normal recipients and examined their capacity to respond to their cognate Ag. Surprisingly, Helios-deficient CD4+ T cells expanded and differentiated into Th1 or Th2 cytokine-producing effectors in a manner similar to wild-type TCR transgenic CD4+ T cells. However, the primed Helios-deficient cells failed to expand upon secondary challenge with Ag. The tolerant state of the Helios-deficient memory T cells was not cell-intrinsic but was due to a small population of Helios-deficient naive T cells that had differentiated into Ag-specific peripheral Treg cells that suppressed the recall response in an Ag-specific manner. These findings demonstrate that Helios plays a role in the determination of CD4+ T cell fate.
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References
-
- Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, and Neurath MF. 2004. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25− T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172: 5149–5153. - PubMed
-
- Zheng SG, Wang J, Wang P, Gray JD, and Horwitz DA. 2007. IL-2 is essential for TGF-beta to convert naive CD4+CD25− cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells. J Immunol 178: 2018–2027. - PubMed
-
- Cobbold SP, Castejon R, Adams E, Zelenika D, Graca L, Humm S, and Waldmann H. 2004. Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol 172: 6003–6010. - PubMed
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