Multimodal human thymic profiling reveals trajectories and cellular milieu for T agonist selection

被引:8
作者
Heimli, Marte [1 ]
Flam, Siri Tennebo [1 ]
Hjorthaug, Hanne Sagsveen [1 ]
Trinh, Don [2 ]
Frisk, Michael [3 ,4 ]
Dumont, Karl-Andreas [5 ]
Ribarska, Teodora [1 ,6 ]
Tekpli, Xavier [1 ]
Saare, Mario [1 ,7 ]
Lie, Benedicte Alexandra [1 ]
机构
[1] Univ Oslo, Oslo Univ Hosp, Dept Med Genet, Oslo, Norway
[2] Oslo Univ Hosp, Dept Pathol, Oslo, Norway
[3] Univ Oslo, Oslo Univ Hosp, Inst Expt Med Res, Oslo, Norway
[4] Univ Oslo, KG Jebsen Ctr Cardiac Res, Oslo, Norway
[5] Oslo Univ Hosp, Dept Cardiothorac Surg, Oslo, Norway
[6] Exact Sci Innovat Ltd, Oxford, England
[7] Univ Tartu, Inst Genom, Tartu, Estonia
来源
FRONTIERS IN IMMUNOLOGY | 2023年 / 13卷
关键词
human thymus; autoimmunity; T cell development; T agonist selection; antigen-presenting cells; single-cell RNA sequencing; spatial transcriptomics; multi-modal; DENDRITIC CELLS; GENE-EXPRESSION; B-CELLS; HASSALLS CORPUSCLES; UBIQUITIN LIGASE; BETA-CATENIN; TCR AFFINITY; INDUCTION; ANTIGEN; OZZ-E3;
D O I
10.3389/fimmu.2022.1092028
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
To prevent autoimmunity, thymocytes expressing self-reactive T cell receptors (TCRs) are negatively selected, however, divergence into tolerogenic, agonist selected lineages represent an alternative fate. As thymocyte development, selection, and lineage choices are dependent on spatial context and cell-to-cell interactions, we have performed Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) and spatial transcriptomics on paediatric human thymu s. Thymocytes expressing markers of strong TCR signalling diverged from the conventional developmental trajectory prior to CD4(+) or CD8(+) lineage commitment, while markers of different agonist selected T cell populations (CD8 alpha alpha(I), CD8 alpha alpha(II), T-(agonist), T-reg(diff), and T-reg) exhibited variable timing of induction. Expression profiles of chemokines and co-stimulatory molecules, together with spatial localisation, supported that dendritic cells, B cells, and stromal cells contribute to agonist selection, with different subsets influencing thymocytes at specific developmental stages within distinct spatial niches. Understanding factors influencing agonist T cells is needed to benefit from their immunoregulatory effects in clinical use.
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页数:25
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