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Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells.

Publication ,  Journal Article
Ng, MSF; Roth, TL; Mendoza, VF; Marson, A; Burt, TD
Published in: Sci Immunol
November 22, 2019

T cell receptor (TCR) stimulation and cytokine cues drive the differentiation of CD4+ naïve T cells into effector T cell populations with distinct proinflammatory or regulatory functions. Unlike adult naïve T cells, human fetal naïve CD4+ T cells preferentially differentiate into FOXP3+ regulatory T (Treg) cells upon TCR activation independent of exogenous cytokine signaling. This cell-intrinsic predisposition for Treg differentiation is implicated in the generation of tolerance in utero; however, the underlying mechanisms remain largely unknown. Here, we identify epigenetic and transcriptional programs shared between fetal naïve T and committed Treg cells that are inactive in adult naïve T cells and show that fetal-derived induced Treg (iTreg) cells retain this transcriptional program. We show that a subset of Treg-specific enhancers is accessible in fetal naïve T cells, including two active superenhancers at Helios Helios is expressed in fetal naïve T cells but not in adult naïve T cells, and fetal iTreg cells maintain Helios expression. CRISPR-Cas9 ablation of Helios in fetal naïve T cells impaired their differentiation into iTreg cells upon TCR stimulation, reduced expression of immunosuppressive genes in fetal iTreg cells such as IL10, and increased expression of proinflammatory genes including IFNG Consequently, Helios knockout fetal iTreg cells had reduced IL-10 and increased IFN-γ cytokine production. Together, our results reveal important roles for Helios in enhancing preferential fetal Treg differentiation and fine-tuning eventual Treg function. The Treg-biased programs identified within fetal naïve T cells could potentially be used to engineer enhanced iTreg populations for adoptive cellular therapies.

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Published In

Sci Immunol

DOI

EISSN

2470-9468

Publication Date

November 22, 2019

Volume

4

Issue

41

Location

United States

Related Subject Headings

  • T-Lymphocytes, Regulatory
  • Ikaros Transcription Factor
  • Humans
  • Cells, Cultured
  • Cell Differentiation
  • CD4-Positive T-Lymphocytes
  • Adult
  • 3204 Immunology
  • 3202 Clinical sciences
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Ng, M. S. F., Roth, T. L., Mendoza, V. F., Marson, A., & Burt, T. D. (2019). Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells. Sci Immunol, 4(41). https://doi.org/10.1126/sciimmunol.aav5947
Ng, Melissa S. F., Theodore L. Roth, Ventura F. Mendoza, Alexander Marson, and Trevor D. Burt. “Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells.Sci Immunol 4, no. 41 (November 22, 2019). https://doi.org/10.1126/sciimmunol.aav5947.
Ng MSF, Roth TL, Mendoza VF, Marson A, Burt TD. Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells. Sci Immunol. 2019 Nov 22;4(41).
Ng, Melissa S. F., et al. “Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells.Sci Immunol, vol. 4, no. 41, Nov. 2019. Pubmed, doi:10.1126/sciimmunol.aav5947.
Ng MSF, Roth TL, Mendoza VF, Marson A, Burt TD. Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells. Sci Immunol. 2019 Nov 22;4(41).

Published In

Sci Immunol

DOI

EISSN

2470-9468

Publication Date

November 22, 2019

Volume

4

Issue

41

Location

United States

Related Subject Headings

  • T-Lymphocytes, Regulatory
  • Ikaros Transcription Factor
  • Humans
  • Cells, Cultured
  • Cell Differentiation
  • CD4-Positive T-Lymphocytes
  • Adult
  • 3204 Immunology
  • 3202 Clinical sciences