Deep profiling of human T cells defines compartmentalized clones and phenotypic trajectories across blood and tonsils

2025/11/26 by Suhas Sureshchandra, James Henderson, Elizabeth Levendosky +18 · 1 voice
Immunology and Microbiology · Biochemistry, Genetics and Molecular Biology · #T-cell and B-cell Immunology #Single-cell and spatial transcriptomics #Immune Cell Function and Interaction

paper · doi:10.1016/j.immuni.2025.10.025

openalex publication_date 2025/11/26 · openalex created_date 2025/11/27 · openalex updated_date 2026/07/23

Abstract

98% of T cells reside in tissues, yet nearly all human T cell analyses are performed on peripheral blood. We performed single-cell sequencing of 5.7 million T cells from autologous blood and tonsils of ten donors. We identified distinct patterns of clonal expansion associated with tonsil-restricted phenotypes. Clonal sharing between blood and tonsils was lower than previous estimates and increased with age. Identical T cell receptor (TCR) sequences exhibited limited concordance in their phenotypes across compartments. Furthermore, location dictated the frequencies, clonal dominance, and phenotypes of antigen-specific T cells. Using immune organoids, we showed that antigen exposure drives functionally distinct T cell clones from naive or tissue-resident memory pools. Finally, we demonstrate that chronic infections influence TCR repertoire diversity differently in blood and tonsil-resident T cells. These data highlight the necessity of accounting for tissue-specific contexts to accurately measure the TCR repertoire and monitor T cell responses following perturbing therapies.

Citations

• Integrated analysis of multimodal single-cell data
• Dictionary learning for integrative, multimodal and scalable single-cell analysis
• The total mass, number, and distribution of immune cells in the human body
• Unbiased estimation of sampling variance for Simpson's diversity index

Discussions

• Our work on these questions has been motivated by our experimental findings uncovering substantial variation in the human immune repertoire across blood and tonsils. doi.org/10.1016/j.im... [bsky, 1 points, 1 comments]

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