Single-cell multiomic analysis of thymocyte development reveals drivers of CD4+ T cell and CD8+ T cell lineage commitment

Steier, Zoë; Aylard, Dominik A.; McIntyre, Laura L.; Baldwin, Isabel; Kim, Esther Jeong Yoon; Lutes, Lydia K.; Ergen, Can; Huang, Tse‐Shun; Robey, Ellen A; Yosef, Nir; Streets, Aaron

doi:10.1038/s41590-023-01584-0

Cited by 18 publications

(17 citation statements)

References 74 publications

(126 reference statements)

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“…Our findings directly align with two recent studies that suggest a slower maturation of CD8 lineage cells 83,85 . Moreover, our observation that co-receptor reversal in CD8 lineage cells coincides with the cortical retention window further indicates that CD8SP thymocytes may require more time to initiate the lineage-specific differentiation programme, which in turn could impact the timing of intercompartmental cell migration.…”

Section: Discussionsupporting

confidence: 92%

A spatial human thymus cell atlas mapped to a continuous tissue axis

Yayon,

Kedlian,

Boehme

et al. 2023

Preprint

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T cells develop from circulating precursors, which enter the thymus and migrate throughout specialised sub-compartments to support maturation and selection. This process starts already in early fetal development and is highly active until the involution of the thymus in adolescence. To map the micro-anatomical underpinnings of this process in pre- vs. post-natal states, we undertook a spatially resolved analysis and established a new quantitative morphological framework for the thymus, the Cortico-Medullary Axis. Using this axis in conjunction with the curation of a multimodal single-cell, spatial transcriptomics and high-resolution multiplex imaging atlas, we show that canonical thymocyte trajectories and thymic epithelial cells are highly organised and fully established by post-conception week 12, pinpoint TEC progenitor states, find that TEC subsets and peripheral tissue genes are associated with Hassall`s Corpuscles and uncover divergence in the pace and drivers of medullary entry between CD4 vs. CD8 T cell lineages. These findings are complemented with a holistic toolkit for spatial analysis and annotation, providing a basis for a detailed understanding of T lymphocyte development.

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Section: Discussionsupporting

confidence: 92%

A spatial human thymus cell atlas mapped to a continuous tissue axis

Yayon,

Kedlian,

Boehme

et al. 2023

Preprint

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“…S4, B and C) detected thymocytes at the DN3 to DN4 transition at the time of ORFTOC graft retrieval, a stage attesting to successful β-selection (Rothenberg, 2021). In addition, DP thymocytes expressing CD69, which indicates positive selection-induced TCR signaling (Steier et al, 2023), were present (Fig. S3 B and D).…”

Section: Resultsmentioning

confidence: 99%

Thymic epithelial organoids mediate T cell development

Hübscher,

Lorenzo-Martín,

Barthlott

et al. 2024

Preprint

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Although the advent of organoids opened unprecedented perspectives for basic and translational research, immune system-related organoids remain largely underdeveloped. Here we established organoids from the thymus, the lymphoid organ responsible for T cell development. We identified conditions enabling thymic epithelial progenitor cell proliferation and development into organoids with in vivo-like transcriptional profiles and diverse cell populations. Contrary to two-dimensional cultures, thymic epithelial organoids maintained thymus functionality in vitro and mediated physiological T cell development upon reaggregation with T cell progenitors. The reaggregates showed in vivo-like epithelial diversity and ability to attract T cell progenitors. Thymic epithelial organoids provide new opportunities to study TEC biology and T cell development in vitro, pave the way for future thymic regeneration strategies and are the first organoids originating from the stromal compartment of a lymphoid organ.

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“…The critical factor influencing lineage selection during T-cell development is the duration of the T-cell receptor (TCR) signaling. Prolonged signals, exemplified by extended exposure to hLR and LR treatment, favor CD4 lineage commitment, while transient signals favor CD8 lineage commitment (Steier et al 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Modulating effects of heat-killed and live Limosilactobacillus reuteri PSC102 on the immune response and gut microbiota of cyclophosphamide-treated rats

Ali,

Lee,

Quah

et al. 2024

Veterinary Quarterly

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In the present study, we investigated the potential immunomodulatory effects of heat-killed (hLR) and live Limosilactobacillus reuteri PSC102 (LR; formerly Lactobacillus reuteri PSC102) in RAW264.7 macrophage cells and Sprague–Dawley rats. RAW264.7 murine macrophage cells were stimulated with hLR and LR for 24 h. Cyclophosphamide (CTX)-induced immunosuppressed Sprague–Dawley rats were orally administered with three doses of hLR (L-Low, M-Medium, and H-High) and LR for 3 weeks. The phagocytic capacity, production of nitric oxide (NO), and expression of cytokines in RAW264.7 cells were measured, and the different parameters of immunity in rats were determined. hLR and LR treatments promoted phagocytic activity and induced the production of NO and the expression of iNOS, TNF-α, IL-1β, IL-6, and Cox-2 in macrophage cells. In the in vivo experiment, hLR and LR treatments significantly increased the immune organ indices, alleviated the spleen injury, and ameliorated the number of white blood cells, granulocytes, lymphocytes, and mid-range absolute counts in immunosuppressive rats. hLR and LR increased neutrophil migration and phagocytosis, splenocyte proliferation, and T lymphocyte subsets (CD4 + , CD8 + , CD45RA + , and CD28 + ). The levels of immune factors (IL-2, IL-4, IL-6, IL-10, IL-12A, TNF-α, and IFN-γ) in the hLR and LR groups were upregulated compared with those in the CTX-treatment group. hLR and LR treatments could also modulate the gut microbiota composition, thereby increasing the relative abundance of Bacteroidetes and Firmicutes but decreasing the level of Proteobacteria. hLR and LR protected against CTX-induced adverse reactions by modulating the immune response and gut microbiota composition. Therefore, they could be used as potential immunomodulatory agents.

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Single-cell multiomic analysis of thymocyte development reveals drivers of CD4+ T cell and CD8+ T cell lineage commitment

Cited by 18 publications

References 74 publications

A spatial human thymus cell atlas mapped to a continuous tissue axis

A spatial human thymus cell atlas mapped to a continuous tissue axis

Thymic epithelial organoids mediate T cell development

Modulating effects of heat-killed and live Limosilactobacillus reuteri PSC102 on the immune response and gut microbiota of cyclophosphamide-treated rats

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