Genetic and epigenetic screens in primary human T cells link candidate causal autoimmune variants to T cell networks

作者：Ching‐Huang Ho, Maxwell A. Dippel, Meghan S. McQuade, LeAnn P. Nguyen, Arpit Mishra, Stephan Pribitzer, Samantha Hardy, Harshpreet Chandok, Florence M. Chardon, Troy A. McDiarmid, Hannah A. DeBerg, Jane H. Buckner, Jay Shendure, Carl G. de Boer, Michael H. Guo, Ryan Tewhey, John Ray · 发表于：Nature Genetics · 年份：2025 · DOI：10.1038/s41588-025-02301-3 · 被引用次数：6 · 研究领域：Diabetes and associated disorders、T-cell and B-cell Immunology、Immune Cell Function and Interaction

Genetic variants associated with autoimmune diseases are highly enriched within putative cis-regulatory regions of CD4+ T cells, suggesting that they could alter disease risk through changes in gene regulation. However, very few genetic variants have been shown to affect T cell gene expression or function. Here we tested >18,000 autoimmune disease-associated variants for allele-specific effects on expression using massively parallel reporter assays in primary human CD4+ T cells. We find 545 variants that modulate expression in an allele-specific manner (emVars). Primary T cell emVars greatly enrich for likely causal variants, are mediated by common upstream pathways and their putative target genes are highly enriched within a lymphocyte activation network. Using bulk and single-cell CRISPR-interference screens, we confirm that emVar-containing T cell cis-regulatory elements modulate both known and previously unappreciated target genes that regulate T cell proliferation, providing plausible mechanisms by which these variants alter autoimmune disease risk. Massively parallel reporter assay in primary human CD4+ T cells and bulk and single-cell CRISPR-interference screens identify candidate causal variants linked to autoimmune disease risk that modulate T cell gene expression and proliferation.