Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Centre for Living Systems, Marseille, France.
Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291-CNRS UMR5051-University Toulouse III, Toulouse, France.
Nat Commun. 2024 Aug 14;15(1):6976. doi: 10.1038/s41467-024-51164-5.
Regulatory T cells (T) are critical players of immune tolerance that develop in the thymus via two distinct developmental pathways involving CD25Foxp3 and CD25Foxp3 precursors. However, the mechanisms regulating the recently identified Foxp3 precursor pathway remain unclear. Here, we find that the membrane-bound lymphotoxin αβ (LTαβ) heterocomplex is upregulated during T development upon TCR/CD28 and IL-2 stimulation. We show that Lta expression limits the maturational development of T from Foxp3 precursors by regulating their proliferation, survival, and metabolic profile. Transgenic reporter mice and transcriptomic analyses further reveal that medullary thymic epithelial cells (mTEC) constitute an unexpected source of IL-4. We demonstrate that LTαβ-lymphotoxin β receptor-mediated interactions with mTEC limit T development by down-regulating IL-4 expression in mTEC. Collectively, our findings identify the lymphotoxin axis as the first inhibitory checkpoint of thymic T development that fine-tunes the Foxp3 T precursor pathway by limiting IL-4 availability.
调节性 T 细胞（T 细胞）是免疫耐受的关键参与者，它们通过涉及 CD25Foxp3 和 CD25Foxp3 前体的两条不同发育途径在胸腺中发育。然而，调节最近发现的 Foxp3 前体途径的机制尚不清楚。在这里，我们发现，在 TCR/CD28 和 IL-2 刺激下，T 细胞发育过程中膜结合的淋巴毒素 αβ（LTαβ）异源复合物上调。我们表明，Lta 的表达通过调节 Foxp3 前体的增殖、存活和代谢特征来限制 T 细胞从前体向成熟的发育。转基因报告小鼠和转录组分析进一步揭示了骨髓胸腺上皮细胞（mTEC）是 IL-4 的意外来源。我们证明，LTαβ-淋巴毒素 β 受体介导的与 mTEC 的相互作用通过下调 mTEC 中的 IL-4 表达来限制 T 细胞的发育。总的来说，我们的研究结果表明，淋巴毒素轴是胸腺 T 细胞发育的第一个抑制性检查点，通过限制 IL-4 的可用性来微调 Foxp3 T 前体途径。
