A single cell reference map for human blood and tissue T cell activation

Human T cells coordinate adaptive immunity by localization in diverse tissue sites, though blood T cells are the most readily studied. We investigated the functional responses of T cells isolated from human lungs (LG), lymph nodes (LN), bone marrow (BM), and blood to TCR-stimulation using single-cell RNA-seq. We defined cellular states for resting T cells including signatures that differentiate tissue and blood T cells and employed new factorization methods to identify activation states conserved across tissues, including an IFN-response activation state in CD4+T cells and distinct effector states specific to CD8+T cells. We demonstrate how this high-resolution map can be used to assess the origin and functional state of T cells in disease by projecting scRNAseq profiles of tumor-associated T cells from multiple cancers, revealing CD8 T cells that co-express markers of exhaustion, activation, and proliferation, and a lack of activated CD4 T cells. Our results establish a high-dimensional reference for human T cell homeostasis and function in multiple sites, from which to probe T cell dysfunction in disease. Overall design: Single-cell RNA-sequencing of control and and anti-CD3/anti-CD28 stimulated T cells from human lung, lymph node, bone marrow and blood.