Work

Single-cell multi-omics reveals archetypal regulatory programs shared across T cell subsets

Year: 2026

Type: article

Abstract: T cells protect against pathogens and tumors and can differentiate into various functionally distinct subsets. While each subset exhibits a characteristic epigenomic and transcriptional profile, essential immune functions such as self-renewal, expansion, cytokine production, and cytotoxicity are common to multiple subsets and therefore must be programmed via shared regulatory mechanisms. To uncover these regulatory “archetypes”, we integrated a new single-cell multiomic (scATAC+RNA-seq) dataset for CD4 and CD8 T cells responding to acute and chronic viral infection with a comprehensive compendium of bulk ATAC-seq data. Our analysis revealed that T cell identity is governed by a modular architecture, where distinct transcription factors drive the reuse of regulatory archetypes across T cell subsets and lineages. Notably, translationally important progenitor Tcf1 + CD8 T cells, critical for sustaining CD8 T cell responses and present in both acute and chronic infection, exhibited a composite regulatory state combining a CD8 T cell exhaustion program and, unexpectedly, a follicular helper CD4 T cell program. In sum, this resource will aid mechanistic dissection of adaptive immunity and immunotherapy design, and the framework will be broadly applicable across biological systems. Highlights – Single-cell multiomics and ATAC-seq atlas reveal T cell regulatory archetypes – A unified progenitor Tcf1 + CD8 T cell population is shared by acute and chronic infection – Progenitor CD8 T cell identity combines CD8 exhaustion and CD4 Tfh regulatory programs – A Tfh-like differentiation gradient underlies heterogeneity in progenitor CD8 T cells

Source: Cell Reports

DOI: 10.1016/j.celrep.2026.118156

Authors: Sarah K. Walker, Joris van der Veeken, Alexander Y. Rudensky, Yuri Pritykin

Institutions: Princeton University, Research Institute of Molecular Pathology, Vienna Biocenter, Memorial Sloan Kettering Cancer Center, Howard Hughes Medical Institute

Language: English

Topic: T-cell and B-cell Immunology

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $5,620