Genes associated with T reg and naïve T cell function are labeled. Clusters are labeled and defined by k-means clustering. (B) Heatmap shows relative expression levels of T reg-specific differentially expressed (DE) genes in AN, FN, AT and FT cells. Boxplots show scores for PC1 (bottom) and PC2 (right). (A) Principal Component Analysis (PCA) plot of RNAseq data comparing adult naïve (AN), fetal naïve (FN), adult T reg (AT) and fetal T reg (FT) cells. The T reg-biased programs identified within fetal naïve T cells could potentially be used to engineer enhanced iT reg populations for adoptive cellular therapies.Ĭopyright © 2019 The Authors, some rights reserved exclusive licensee American Association for the Advancement of Science. Together, our results reveal important roles for Helios in enhancing preferential fetal T reg differentiation and fine-tuning eventual T reg function. CRISPR-Cas9 ablation of Helios in fetal naïve T cells impaired their differentiation into iT reg cells upon TCR stimulation, reduced expression of immunosuppressive genes in fetal iT reg cells such as IL10, and increased expression of proinflammatory genes including IFNG Consequently, Helios knockout fetal iT reg cells had reduced IL-10 and increased IFN-γ cytokine production. We show that a subset of T reg-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 iT reg cells maintain Helios expression. Here, we identify epigenetic and transcriptional programs shared between fetal naïve T and committed T reg cells that are inactive in adult naïve T cells and show that fetal-derived induced T reg (iT reg) cells retain this transcriptional program.
This cell-intrinsic predisposition for T reg differentiation is implicated in the generation of tolerance in utero however, the underlying mechanisms remain largely unknown. Unlike adult naïve T cells, human fetal naïve CD4 + T cells preferentially differentiate into FOXP3 + regulatory T (T reg) cells upon TCR activation independent of exogenous cytokine signaling. 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. 12 Department of Pediatrics, Division of Neonatology, UCSF, San Francisco, CA 94110, USA. 11 Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, CA 94143, USA.10 Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA.9 UCSF Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA 94158, USA.8 Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
7 Department of Medicine, UCSF, San Francisco, CA 94143, USA.6 Innovative Genomics Institute, University of California, Berkeley, CA 94720, USA.5 Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, CA 94143, USA.
4 Diabetes Center, UCSF, San Francisco, CA 94143, USA.3 Department of Microbiology and Immunology, UCSF, San Francisco, CA 94143, USA.2 Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis, Singapore 138648, Singapore.1 Biomedical Sciences Graduate Program, University of California, San Francisco (UCSF), San Francisco, CA 94143, USA.
0 kommentar(er)
