Centre d'Immunophénomique (CIPHE), Aix Marseille Université, INSERM, CNRS UMR, Marseille, France.
Centre d'Immunologie de Marseille-Luminy (CIML), Aix Marseille Université, INSERM, CNRS, Marseille, France.
EMBO J. 2022 Mar 1;41(5):e110023. doi: 10.15252/embj.2021110023. Epub 2022 Feb 7.
After entering the adult thymus, bipotent T-cell progenitors give rise to αβ or γδ T cells. To determine whether the γδ T-cell receptor (TCR) has an instructive role in γδ T-cell lineage commitment or only "confirms" a pre-established γδ Τ-cell lineage state, we exploited mice lacking expression of LAT, an adaptor required for γδ TCR signaling. Although these mice showed a T-cell development block at the CD4 CD8 double-negative third (DN3) stage, 0.3% of their DN3 cells expressed intermediate levels of γδ TCR (further referred to as γδ ) at their surface. Single-cell transcriptomics of LAT-deficient DN3 γδ cells demonstrated no sign of commitment to the γδ T-cell lineage, apart from γδ TCR expression. Although the lack of LAT is thought to tightly block DN3 cell development, we unexpectedly found that 25% of LAT-deficient DN3 γδ cells were actively proliferating and progressed up to the DN4 stage. However, even those cells failed to turn on the transcriptional program associated with the γδ T-cell lineage. Therefore, the γδ TCR-LAT signaling axis builds upon a γδ T-cell uncommitted lineage state to fully instruct adult γδ T-cell lineage specification.
进入成人胸腺后，双潜能 T 细胞祖细胞产生 αβ 或 γδ T 细胞。为了确定 γδ T 细胞受体 (TCR) 是否在 γδ T 细胞谱系决定中具有指导作用，还是仅“证实”已预先建立的 γδ Τ 细胞谱系状态，我们利用缺乏衔接蛋白 LAT 表达的小鼠，该蛋白是 γδ TCR 信号所必需的。尽管这些小鼠在 CD4 CD8 双阴性第三 (DN3) 阶段出现 T 细胞发育阻滞，但它们的 0.3% DN3 细胞在其表面表达中等水平的 γδ TCR（进一步称为 γδ）。LAT 缺陷型 DN3 γδ 细胞的单细胞转录组学表明，除了 γδ TCR 表达外，没有向 γδ T 细胞谱系分化的迹象。尽管缺乏 LAT 被认为会严格阻断 DN3 细胞发育，但我们出人意料地发现，25%的 LAT 缺陷型 DN3 γδ 细胞正在积极增殖，并进展到 DN4 阶段。然而，即使是这些细胞也未能开启与 γδ T 细胞谱系相关的转录程序。因此，γδ TCR-LAT 信号轴建立在未分化的 γδ T 细胞谱系状态之上，以完全指导成人 γδ T 细胞谱系的特化。
