Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease

TLDR

Human T cells coordinate adaptive immunity in diverse anatomic compartments through production of cytokines and effector molecules, but it is unclear how tissue site influences T cell persistence and function. Here, we use single cell RNA‑sequencing (scRNA‑seq) to define the heterogeneity of human T cells isolated from lungs, lymph nodes, bone marrow and blood, and their functional responses following stimulation. We performed scRNA‑seq on >50,000 resting and activated T cells from these tissues to map tissue‑specific signatures and activation states. We identified tissue‑specific T cell signatures in mucosal and lymphoid sites, lineage‑specific activation states including distinct CD8⁺ effector states and an interferon‑response state for CD4⁺ T cells, and found that tumor‑associated T cells predominantly exhibit activated CD8⁺ states compared to CD4⁺ states, establishing a high‑dimensional reference map of human T cell activation in health for disease analysis.

Abstract

Human T cells coordinate adaptive immunity in diverse anatomic compartments through production of cytokines and effector molecules, but it is unclear how tissue site influences T cell persistence and function. Here, we use single cell RNA-sequencing (scRNA-seq) to define the heterogeneity of human T cells isolated from lungs, lymph nodes, bone marrow and blood, and their functional responses following stimulation. Through analysis of >50,000 resting and activated T cells, we reveal tissue T cell signatures in mucosal and lymphoid sites, and lineage-specific activation states across all sites including distinct effector states for CD8+ T cells and an interferon-response state for CD4+ T cells. Comparing scRNA-seq profiles of tumor-associated T cells to our dataset reveals predominant activated CD8+ compared to CD4+ T cell states within multiple tumor types. Our results therefore establish a high dimensional reference map of human T cell activation in health for analyzing T cells in disease.