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Sci Immunol. 2019 Nov 22;4(41). pii: eaav5947. doi: 10.1126/sciimmunol.aav5947.

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

Ng MSF1,2, Roth TL1,3,4, Mendoza VF5, Marson A3,4,6,7,8,9,10, Burt TD11,12.

Author information

1
Biomedical Sciences Graduate Program, University of California, San Francisco (UCSF), San Francisco, CA 94143, USA.
2
Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis, Singapore 138648, Singapore.
3
Department of Microbiology and Immunology, UCSF, San Francisco, CA 94143, USA.
4
Diabetes Center, UCSF, San Francisco, CA 94143, USA.
5
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, CA 94143, USA.
6
Innovative Genomics Institute, University of California, Berkeley, CA 94720, USA.
7
Department of Medicine, UCSF, San Francisco, CA 94143, USA.
8
Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
9
UCSF Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA 94158, USA.
10
Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA.
11
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, CA 94143, USA. trevor.burt@duke.edu.
12
Department of Pediatrics, Division of Neonatology, UCSF, San Francisco, CA 94110, USA.

Abstract

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.

PMID:
31757834
DOI:
10.1126/sciimmunol.aav5947

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