Scientists have produced a large functional map of the human immune system by systematically disrupting nearly 13,000 genes in 22 million primary CD4 T cells and recording how each change altered cellular activity. The peer-reviewed study, published in Cell and announced on August 28, moves beyond identifying DNA sequences to show how genes influence one another inside immune cells, according to Gladstone Institutes, UC San Francisco and Stanford University researchers working with Biohub.
The team used cells obtained from four human blood donors rather than relying only on laboratory cell lines. Researchers examined the cells both at rest and after stimulation, allowing them to compare gene networks across different immune states. CD4 T cells coordinate many immune responses, making their regulatory circuitry relevant to infections, cancer and autoimmune disorders, although the new work does not itself establish a treatment.
To build the map, the researchers combined CRISPR-based gene disruption with a probe-based form of Perturb-seq. In this approach, a genetic instruction disables a selected gene and single-cell RNA measurements capture the resulting changes in gene expression. Repeating that process at exceptional scale enabled the team to connect regulators with downstream genes and construct networks rather than a simple list of genetic parts.
The study's scale addresses a central limitation in genomics: sequencing can associate a variant with disease, but often cannot explain what that variant does in a living human cell. Testing almost every gene expressed in these donor-derived T cells provides evidence of cause and effect under controlled conditions. The resulting data can help researchers prioritize mechanisms for further experiments and interpret genetic variants linked to immune disease.
Gladstone said the dataset is the largest contribution so far to the Billion Cells Project, an initiative designed to generate single-cell data for biological research and artificial-intelligence models. The participating institutions include Gladstone, UCSF, Stanford, Biohub, the Arc Institute, the Innovative Genomics Institute, the Parker Institute for Cancer Immunotherapy, the University of Tokyo and other partners. The Cell paper carries the DOI 10.1016/j.cell.2026.08.002.
Researchers said the framework may eventually guide more precise cancer immunotherapies or approaches to autoimmune disease by revealing which genetic switches control useful or harmful T-cell behavior. Those applications remain prospective: the present result is a research atlas built from cells studied outside the body, not proof of safety or efficacy in patients. The next task is to test promising circuits in additional donors, immune-cell types and disease settings.
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