Single-cell multiomics reveals archetypal regulatory programs shared across CD4 and CD8 T cell subsets in viral infection

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.