Deep profiling of human T cells defines compartmentalized clones and phenotypic trajectories across blood and tonsils
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.
Authors
- Gurpreet S. Ahuja (ORCID: https://orcid.org/0000-0002-3196-0819)
- Lisa E. Wagar (ORCID: https://orcid.org/0000-0001-5980-3586)
- Jenna M. Kastenschmidt (ORCID: https://orcid.org/0000-0002-0067-5142)
- Elizabeth Levendosky (ORCID: https://orcid.org/0000-0001-6230-1851)
- Chandrani Thakur (ORCID: https://orcid.org/0000-0003-2833-0610)
- Samuel J. H. Murphy (ORCID: https://orcid.org/0000-0002-5694-3572)
- Andrew M. Sorn (ORCID: https://orcid.org/0000-0001-8660-1533)
- Suhas Sureshchandra (ORCID: https://orcid.org/0000-0002-4141-8564)
- Mahina Tabassum Mitul (ORCID: https://orcid.org/0000-0002-5344-6810)
- Annie Moisan (ORCID: https://orcid.org/0000-0002-4944-4548)
- Aviv I. Benchorin
- Naresha Saligrama (ORCID: https://orcid.org/0000-0003-2526-7150)
- Allyssa L. Daugherty (ORCID: https://orcid.org/0000-0001-8428-0422)
- Douglas K. Trask (ORCID: https://orcid.org/0000-0003-0550-442X)
- James Henderson (ORCID: https://orcid.org/0000-0003-3714-4799)
- Timothy B. Yates
- Andreas Tiffeau-Mayer
- Qiu Zhong (ORCID: https://orcid.org/0009-0008-1928-3051)
- Evien Cheng
- Kyle Batucal
- Sankalan Bhattacharyya
Institutions
- Children's Hospital of Orange County (US)
- University of California, Irvine (US)
- Ascom (Switzerland) (CH)
- Hope Center for Neurological Disorders (US)
- Irvine University (US)
- Institute of Infection and Immunity (CA)
- University College London (GB)
Publication Details
- Journal
- Immunity
- Published
- 2025-11-26
- DOI
- https://doi.org/10.1016/j.immuni.2025.10.025
- Citations
- 5
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 3.99