Innate- like T cell subset commitment in the murine thymus is independent of TCR characteristics and occurs during proliferation

• 成果类型: Article
• 署名作者: Karnaukhov, Vadim K.; Gac, Anne- Laure Le; Mutala, Linda Bilonda; Darbois, Aurelie; Perrin, Laetitia; Legoux, Francois; Walczak, Aleksandra M.; Mora, Thierry; Lantz, Olivier
• 署名单位: Universite PSL; UNICANCER; Institut Curie; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Universite PSL; Ecole Normale Superieure (ENS); Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universite de Rennes; UNICANCER; Universite PSL; Institut Curie; Institut National de la Sante et de la Recherche Medicale (Inserm)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13055
• DOI: 10.1073/pnas.2311348121
• 发表日期: 2024-04-04
• 关键词: cd4(+); differentiation; repertoire; mechanisms; expression; selection; distinct; signals

摘要

How T- cell receptor (TCR) characteristics determine subset commitment during T- cell development is still unclear. Here, we addressed this question for innate- like T cells, mucosal- associated invariant T (MAIT) cells, and invariant natural killer T (iNKT) cells. MAIT and iNKT cells have similar developmental paths, leading in mice to two effector subsets, cytotoxic (MAIT1/iNKT1) and IL17- secreting (MAIT17/iNKT17). For iNKT1 vs iNKT17 fate choice, an instructive role for TCR affinity was proposed but recent data argue against this model. Herein, we examined TCR role in MAIT and iNKT subset commitment through scRNAseq and TCR repertoire analysis. In our dataset of thymic MAIT cells, we found pairs of T- cell clones with identical amino acid TCR sequences originating from distinct precursors, one of which committed to MAIT1 and the other to MAIT17 fates. Quantitative in silico simulations indicated that the number of such cases is best explained by lineage choice being independent of TCR characteristics. Comparison of TCR features of MAIT1 and MAIT17 clonotypes demonstrated that the subsets cannot be distinguished based on TCR sequence. To pinpoint the developmental stage associated with MAIT sublineage choice, we demonstrated that proliferation takes place both before and after MAIT fate commitment. Altogether, we propose a model of MAIT cell development in which noncommitted, intermediate- stage MAIT cells undergo a first round of proliferation, followed by TCR characteristics- independent commitment to MAIT1 or MAIT17 lineage, followed by an additional round of proliferation. Reanalyzing a published iNKT TCR dataset, we showed that this model is also relevant for iNKT cell development.