内含子增强子诱导NFATc1限制NKTγδ细胞的形成。
NFATc1 induction by an intronic enhancer restricts NKT γδ cell formation.
作者信息
Giampaolo Sabrina, Chiarolla Cristina M, Knöpper Konrad, Vaeth Martin, Klein Matthias, Muhammad Azeem, Bopp Tobias, Berberich-Siebelt Friederike, Patra Amiya K, Serfling Edgar, Klein-Hessling Stefan
机构信息
Institute of Pathology, Julius Maximilians University Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany.
Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-University Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
出版信息
iScience. 2023 Feb 19;26(3):106234. doi: 10.1016/j.isci.2023.106234. eCollection 2023 Mar 17.
In thymus, the ablation of T cell receptor (TCR)-activated transcription factor NFATc1 or its inducible isoforms during the double-negative (DN) stages of thymocyte development leads to a marked increase in γδ thymocytes whereas the development of αβ thymocytes remains mostly unaffected. These γδ thymocytes are characterized by the upregulation of the promyelocytic leukemia zinc-finger factor (PLZF), the "master regulator" of natural killer T (NKT) cell development, and the acquisition of an NKT γδ cell phenotype with higher cell survival rates. The suppressive function of NFATc1 in NKT γδ cell formation critically depends on the remote enhancer E2, which is essential for the inducible expression of NFATc1 directed by its distal promoter P1. Thus, the enhancer deciphers a strong γδ TCR signal into the expression of inducible NFATc1 isoforms resulting in high levels of NFATc1 protein that are essential to control the numbers of NKT γδ cells.
在胸腺中，在胸腺细胞发育的双阴性（DN）阶段，T细胞受体（TCR）激活的转录因子NFATc1或其诱导型异构体的缺失会导致γδ胸腺细胞显著增加，而αβ胸腺细胞的发育大多不受影响。这些γδ胸腺细胞的特征是早幼粒细胞白血病锌指因子（PLZF）上调，PLZF是自然杀伤T（NKT）细胞发育的“主调节因子”，并且获得了具有更高细胞存活率的NKT γδ细胞表型。NFATc1在NKT γδ细胞形成中的抑制功能关键取决于远端增强子E2，E2对于由其远端启动子P1指导的NFATc1的诱导表达至关重要。因此，增强子将强烈的γδ TCR信号解码为诱导型NFATc1异构体的表达，从而导致高水平的NFATc1蛋白，这对于控制NKT γδ细胞的数量至关重要。
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