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Genome-scale perturb-seq in primary human CD4+ T cells maps context-specific regulators of T cell programs and human immune traits

  • Ronghui Zhu1
  • Emma Dann2
  • Jun Yan3
  • Justine Reyes Retana3
  • Ryunosuke Goto4
  • Reese C Guitche5
  • Lillian Brixi6
  • Mineto Ota7
  • Austin Hartman8
  • Theodore L. Roth9
  • Ansuman T. Satpathy10
  • Jonathan K. Pritchard11
1 more authors
  • Alexander Marson
11 affiliations
  1. 1Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. Electronic address: [email protected]
  2. 2Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. Electronic address: [email protected]
  3. 3Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA
  4. 4Department of Biomedical Data Science, Stanford University, Stanford, CA, USA
  5. 5Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; University of San Francisco, San Francisco, CA, USA
  6. 6Department of Genetics, Stanford University, Stanford, CA, USA
  7. 7Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA; Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  8. 8Department of Genetics, Stanford University, Stanford, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA; Arc Institute, Palo Alto, CA, USA
  9. 9Department of Pathology, Stanford University, Stanford, CA, USA; Arc Institute, Palo Alto, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Weill Foundation West Coast Cancer Hub, Stanford, CA, USA
  10. 10Department of Genetics, Stanford University, Stanford, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Weill Foundation West Coast Cancer Hub, Stanford, CA, USA
  11. 11Department of Genetics, Stanford University, Stanford, CA, USA; Department of Biology, Stanford University, Stanford, CA, USA. Electronic address: [email protected]
Open at sourceDOICite

Abstract

Gene regulatory networks encode the fundamental logic of cellular functions, but systematic network mapping remains challenging, especially in cell states relevant to human biology and disease. Here, we perturbed all expressed genes across 22 million primary human CD4+ T cells from four donors and developed a probe-based perturb-seq platform to measure the transcriptome effects in cells at rest and after stimulation. These data allow us to map genes that regulate known and novel pathways, including novel regulators of cytokine production. Importantly, active regulators and the gene programs they control change dramatically across stimulation conditions. Perturbation signatures enabled us to model T cell states observed in population-scale transcriptomic atlases, nominating regulators of Th1 and Th2 polarization and of age-related T cell phenotypes. Finally, we leveraged perturb-seq to implicate context-specific gene regulatory pathways in autoimmune disease risk. Our data provide a foundational resource to decode human immune function and genetic variation and for new approaches to study gene regulatory networks.

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Cite

BibTeXRIS
BibTeX
@article{zhu2026genomescale,
  title = {{Genome-scale perturb-seq in primary human CD4+ T cells maps context-specific regulators of T cell programs and human immune traits}},
  author = {Ronghui Zhu and Emma Dann and Jun Yan and Justine Reyes Retana and Ryunosuke Goto and Reese C Guitche and Lillian Brixi and Mineto Ota and Austin Hartman and Theodore L. Roth and Ansuman T. Satpathy and Jonathan K. Pritchard and Alexander Marson},
  journal = {Cell},
  year = {2026},
  month = aug,
  doi = {10.1016/j.cell.2026.08.002},
  url = {https://doi.org/10.1016/j.cell.2026.08.002},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Genome-scale perturb-seq in primary human CD4+ T cells maps context-specific regulators of T cell programs and human immune traits
AU  - Ronghui Zhu
AU  - Emma Dann
AU  - Jun Yan
AU  - Justine Reyes Retana
AU  - Ryunosuke Goto
AU  - Reese C Guitche
AU  - Lillian Brixi
AU  - Mineto Ota
AU  - Austin Hartman
AU  - Theodore L. Roth
AU  - Ansuman T. Satpathy
AU  - Jonathan K. Pritchard
AU  - Alexander Marson
PY  - 2026
DA  - 2026/08/01
JO  - Cell
DO  - 10.1016/j.cell.2026.08.002
UR  - https://doi.org/10.1016/j.cell.2026.08.002
AB  - Gene regulatory networks encode the fundamental logic of cellular functions, but systematic network mapping remains challenging, especially in cell states relevant to human biology and disease. Here, we perturbed all expressed genes across 22 million primary human CD4+ T cells from four donors and developed a probe-based perturb-seq platform to measure the transcriptome effects in cells at rest and after stimulation. These data allow us to map genes that regulate known and novel pathways, including novel regulators of cytokine production. Importantly, active regulators and the gene programs they control change dramatically across stimulation conditions. Perturbation signatures enabled us to model T cell states observed in population-scale transcriptomic atlases, nominating regulators of Th1 and Th2 polarization and of age-related T cell phenotypes. Finally, we leveraged perturb-seq to implicate context-specific gene regulatory pathways in autoimmune disease risk. Our data provide a foundational resource to decode human immune function and genetic variation and for new approaches to study gene regulatory networks.
SN  - 0092-8674
SN  - 1097-4172
ER  -