The CD8 immgenT framework as a universal reference of mouse CD8 T cell differentiation states
Mouse CD8 T cell differentiation has been studied extensively in models of infections and cancer, yet no unified framework spans the full spectrum of immunological contexts. Here, we present the CD8 immgenT framework, integrating >200,000 single-cell transcriptomes and 128-plex surface proteomes from 734 samples across 45 perturbations, 45 tissues, and multiple timepoints. Unbiased analysis resolves 21 robust, recurrent states that capture naive, effector, circulating memory, tissue-resident memory, progenitor-exhausted, and terminally exhausted compartments, among others. These states reproducibly re-emerge with striking molecular convergence across acute and chronic infections, cancer, autoimmunity, aging, and homeostasis, revealing that highly similar transcriptional programs are deployed in dramatically different immunological contexts and can support protective or dysfunctional functions depending on developmental history and microenvironmental cues. Classic archetypes map to discrete clusters yet display previously unappreciated heterogeneity and extensive overlap, cautioning against rigid application of legacy subset nomenclature. We provide validated combinatorial markers, flow cytometry gating strategies, and T cell reference-based integration, a projection tool for reproducible annotation of new datasets. The CD8 immgenT framework thus establishes a universal coordinate system for mouse CD8 T cell biology that harmonizes fragmented literature and clarifies biological relationships across the entire spectrum of immune challenges. Overall design: Syngeneic MC38-SIY colon carcinoma and B16-SIY melanoma tumors were implanted subcutaneously in C57BL/6 mice. Tumors were harvested 14 days post-implantation, enzymatically digested, and live CD45? immune cells were isolated by flow cytometric sorting. Single-cell 3' gene expression libraries were generated to profile immune cell transcriptional states within the tumor microenvironment.