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.
Highlights
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
Tissue site was a source of variability; T cells from bone marrow (BM) and lymph nodes (LN) co-localized while LG T cells were more distinct (Fig. 1b), consistent with a greater proportion of CD8+ T cells and TRM phenotype cells in LG relative to the two lymphoid sites (Supplementary Fig. 2 and previous studies10,13,32)
Human T cells persist in distinct anatomic sites, maintain protective immunity and surveillance, and are key targets for immune modulation in tumor immunotherapy, transplantation, and autoimmunity
Summary
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. Activation of naive T cells through the antigen-specific T cell receptor (TCR) initiates transcriptional programs that drive differentiation of lineagespecific effector functions; CD4+ T cells secrete cytokines to recruit and activate other immune cells while CD8+ T cells acquire cytotoxic functions to directly kill infected or tumor cells Most of these effector cells are short-lived, some develop into long-lived memory T cells which persist as circulating central (TCM) and effector-memory (TEM) subsets, and non-circulating tissue resident memory T cells (TRM) in diverse lymphoid and non-lymphoid sites[1,2,3,4]. Single cell transcriptome profiling (scRNA-seq) has enabled high resolution mapping of cellular heterogeneity, development, and activation states in diverse systems[23,24] This approach has been applied to analyze human T cells in diseased tissues[25,26] and in response to immunotherapies in cancer[27]; baseline functional profiles of human T cells in healthy blood and tissues would be an important reference dataset. We have established a tissue resource where we obtain multiple lymphoid, mucosal, and other peripheral tissue sites from human organ donors[9,10,11,13,28,29], enabling study of T cells across different anatomical spaces
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