Genome-scale perturb-seq in primary human CD4 + T cells maps context-specific regulators of T cell programs and human immune traits.
Level 5 - mechanism / opinion, no new human data
In vitro laboratory screening study in primary human cells without clinical outcomes
PubMed 42664972 · doi:10.1016/j.cell.2026.08.002
What was done
The authors developed a probe-based Perturb-seq platform to systematically perturb all expressed genes across 22 million primary human CD4+ T cells from four donors. Transcriptomic responses were profiled under resting conditions and following stimulation to map context-specific gene regulatory networks.
What was found
The screen mapped context-dependent regulators of immune pathways, including previously uncharacterized regulators of cytokine production. Active gene regulatory networks shifted substantially across stimulation states. Perturbation signatures were integrated with population transcriptomic atlases to nominate regulators of T cell polarization, age-associated phenotypes, and autoimmune disease risk. The abstract reports no numerical effect sizes or gene-specific statistics beyond the 22 million cells and four donors.
Why it matters
This work provides a genome-scale functional regulatory atlas in primary human T cells across resting and stimulated states, offering a foundational platform to link functional cellular perturbations with human immune trait genetics.
Limits
The study is restricted to in vitro bench assays using cells from only four donors. Specific quantitative effect sizes, clinical correlates, and downstream in vivo validations are not detailed in the abstract.
Cited by
- supports Alex Marson's laboratory released a functional genomics dataset mapping the single-cell RNA sequencing profiles of 22 million primary human immune cells with CRISPR gene knockouts.