Helios Deficiency Predisposes the Differentiation of CD4 + Foxp3 - T Cells into Peripherally Derived Regulatory T Cells

• Published in: The Journal of immunology (1950) Vol. 203; no. 2; pp. 370 - 378
• Main Authors: Skadow, Mathias, Penna, Vinay R, Galant-Swafford, Jessica, Shevach, Ethan M, Thornton, Angela M
• Format: Journal Article
• Language: English
• Published: United States 15.07.2019
• Subjects: Animals; Autoimmunity - immunology; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation - immunology; Disease Susceptibility - immunology; DNA-Binding Proteins - deficiency; Forkhead Transcription Factors - immunology; Lymphocyte Activation - immunology; Mice; Mice, Inbred C57BL; T-Lymphocytes, Regulatory - immunology; Transcription Factors - deficiency
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1900388

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.