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Vaccines and Immunoinformatics Approaches · Journal article
The Journal of Immunology · July 28, 2026
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This is a mechanistic study combining single-cell multiome profiling of human fetal and pediatric thymic tissue with CRISPR-Cas9 knockout validation to map gene regulatory networks controlling CD4+ Treg differentiation. The work identifies candidate driver transcription factors (FOXP3, REL, IKZF2, IRF4, FOXO1, BATF) in thymic Tregs but remains at the discovery and validation stage in primary cells without functional or clinical endpoints.
Single-cell multiome atlas with CRISPR-Cas9 knockout validation in primary cells. Human fetal and pediatric thymic tissue samples; primary human thymocytes used for functional validation.. Intervention: CRISPR-Cas9 knockout of candidate transcription factors (IRF4, REL, FOXO1, BATF, and others) in primary human thymocytes.. Compared with: Comparison of gene regulatory networks between mature CD4+ Tregs and conventional CD4+ T cells..
GRN analysis identified key driver TFs including FOXP3, REL, and IKZF2 within CD4+ Tregs Comparison of GRNs between mature CD4+ Tregs and conventional CD4+ T cells revealed TFs related to TCR signaling and novel TFs Candidate TFs including IRF4, REL, FOXO1, BATF and others were validated using CRISPR-Cas9 KO in primary human thymocytes
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This work provides mechanistic insight into Treg lineage commitment but does not yet demonstrate how these findings will improve Treg-based therapies or overcome the instability and plasticity problems noted in the introduction. Further functional and translational studies are needed to bridge from network mapping to therapeutic application.
Single-cell mechanistic study identifying transcription factor networks in thymic Treg development with CRISPR validation in primary cells, but lacks clinical outcomes or disease models needed to establish therapeutic relevance.
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This work provides mechanistic insight into Treg lineage commitment but does not yet demonstrate how these findings will improve Treg-based therapies or overcome the instability and plasticity problems noted in the introduction. Further functional and translational studies are needed to bridge from network mapping to therapeutic application.
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Abstract Introduction CD4+ regulatory T cells (Tregs) are essential for maintaining immune homeostasis and preventing autoimmunity. Tregs primarily develop in the thymus, but can also arise from naïve CD4+ T cells in the periphery (pTregs) or be generated in vitro (iTregs). However, a major limitation of Treg-based therapies is the instability and plasticity of pTregs and iTregs. In contrast, tTregs have been shown to exhibit stable suppressive capacity, largely due to thymic-derived signals that epigenetically reinforce the Treg program. Elucidating the mechanisms governing Treg differentiation, stability, and function is therefore critical for improving Treg-based therapies. Methods We generated single-cell multiome data from human fetal and pediatric thymuses. We developed various analytical frameworks for unravelling gene regulatory networks (GRNs) involved in Treg lineage commitment. We identified candidate transcription factors (TFs) involved in thymic Treg differentiation and validated these TFs using a CRISPR-Cas9 KO system in primary human thymocytes. Results GRN analysis revealed key driver TFs, such as FOXP3, REL and IKZF2 within CD4+ Tregs. Comparison of GRNs between mature CD4+ Tregs and conventional CD4+ T cells further reveals TFs related to TCR signaling and other novel TFs. Finally, candidate TFs including IRF4, REL, FOXO1, BATF and others were validated utilizing a CRISPR-Cas9 KO system. Conclusion We generated a single cell multiome atlas of fetal and pediatric thymuses and unravel GRNs involved in Treg lineage-specific differentiation. We develop novel analytical frameworks to identify lineage-specific driver TFs in Tregs and validated these by KO of primary human thymocytes. This framework provides an important mapping of GRNs involved in thymic T cell differentiation, particularly focusing on Tregs and will serve as an important basis for understanding Treg biology and improving Treg-based therapies. Funding Source Creative-Pioneering Researchers Program (800-20230490) Seoul National University Topic Categories Hematopoiesis and Immune System Development (HEM)
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