The Regulators

We built a reproducible discovery-to-target pipeline using a genome-scale CRISPRi Perturb-seq atlas of primary human CD4+ T cells (Marson 2025), scoring every perturbation along two axes: T-cell activation and Th1/Th2 polarization. We benchmarked each axis against the authors' published regulator coefficients before ranking any candidates. The polarization axis showed strong concordance (Spearman ρ = 0.72; AUROC = 0.92 for known regulators), with directional agreement across 21 established Th1/Th2 regulators; the activation axis showed weak concordance (ρ = 0.13) and was therefore retained as exploratory only. The validated polarization axis recovered established immunoregulatory targets in the expected direction, including IFNAR1, the target of approved anifrolumab, and TNFRSF9, a therapeutically pursued immunoregulatory target. The central finding is a trade-off between novelty and tractability: the most reproducible potentially novel hits are intracellular scaffolds and chromatin factors that are difficult to drug. TATDN2 emerged as our strongest potentially novel lead: its knockdown produced a reproducible Th2-skewing phenotype, and it is annotated as a metal-dependent nuclease with a potentially tractable catalytic pocket. These results generate testable target hypotheses for allergic and atopic disease and for Th1-driven autoimmune conditions such as MS, IBD, and RA, while leaving the indication-specific therapeutic direction to be established experimentally.

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