Nr4a1 and Nr4a3 Reporter Mice Are Differentially Sensitive to T Cell Receptor Signal Strength and Duration.
Nr4a1 and Nr4a3 Reporter Mice Are Differentially Sensitive to T Cell Receptor Signal Strength and Duration.
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DOI：
10.1016/j.celrep.2020.108328
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发表时间：
2020-11-03
期刊：
影响因子：
8.8
通讯作者：
Bending D
中科院分区：
文献类型：
--
作者：
Jennings E;Elliot TAE;Thawait N;Kanabar S;Yam-Puc JC;Ono M;Toellner KM;Wraith DC;Anderson G;Bending D
Nr 4a受体由T细胞受体（TCR）信号传导激活，并且在T细胞分化中起关键作用。哪些TCR信号通路调节Nr 4a受体及其对TCR信号强度和持续时间的敏感性仍不清楚。使用Nr 4a 1/Nur 77-GFP和Nr 4a 3-Timer的细胞动力学和活动（Tocky）小鼠，我们阐明了控制Nr 4a受体表达的信号通路。我们发现Nr 4a 1-Nr 4a 3是Src家族激酶依赖性的。此外，Nr 4a 2和Nr 4a 3被钙调磷酸酶抑制剂减弱并结合活化T细胞核因子1（NFAT 1），突出了NFAT 1在Nr 4a 2和Nr 4a 3的控制中的必要和充分的作用，但Nr 4a 1是冗余的。Nr 4a 1-GFP在T细胞发育过程中被紧张和同源信号激活，而Nr 4a 3-Tocky需要同源肽：主要组织相容性复合体（MHC）相互作用才能表达。与Nr 4a 3-Tocky相比，Nr 4a 1-GFP对TCR信号传导的敏感性约为2至3倍，并且可通过较短的TCR信号传导周期检测到。这些发现表明，TCR信号持续时间可能是一个未被充分认识的方面，影响体内T细胞的发育命运。Nr 4a 1和Nr 4a 3显示对钙调磷酸酶/NFAT途径的差异依赖性Nr 4a 1-GFP在胸腺内发育中的Tcon和Treg中表达Nr 4a 3-Timer表达主要限于胸腺和外周CD 25 + Treg Nr 4a 3-Timer需要更强和/或更长的TCR信号用于其表达Nr 4a报告小鼠是研究TCR信号传导的有用工具。Jennings等人显示Nr 4a 3而不是Nr 4a 1是NFAT途径依赖性，导致T细胞发育期间Nr 4a 3-Timer表达受限。Nr 4a 3-Timer需要比Nr 4a 1-GFP更强和/或更长的TCR信号，允许在体内研究不同的TCR信号传导等级。
Nr4a receptors are activated by T cell receptor (TCR) signaling and play key roles in T cell differentiation. Which TCR signaling pathways regulate Nr4a receptors and their sensitivities to TCR signal strength and duration remains unclear. Using Nr4a1/Nur77-GFP and Nr4a3-Timer of cell kinetics and activity (Tocky) mice, we elucidate the signaling pathways governing Nr4a receptor expression. We reveal that Nr4a1–Nr4a3 are Src family kinase dependent. Moreover, Nr4a2 and Nr4a3 are attenuated by calcineurin inhibitors and bind nuclear factor of activated T cells 1 (NFAT1), highlighting a necessary and sufficient role for NFAT1 in the control of Nr4a2 and Nr4a3, but redundancy for Nr4a1. Nr4a1-GFP is activated by tonic and cognate signals during T cell development, whereas Nr4a3-Tocky requires cognate peptide:major histocompatibility complex (MHC) interactions for expression. Compared to Nr4a3-Tocky, Nr4a1-GFP is approximately 2- to 3-fold more sensitive to TCR signaling and is detectable by shorter periods of TCR signaling. These findings suggest that TCR signal duration may be an underappreciated aspect influencing the developmental fate of T cells in vivo. Nr4a1 and Nr4a3 show differential dependency on the calcineurin/NFAT pathway Nr4a1-GFP is expressed in developing Tcon and Treg within the thymus Nr4a3-Timer expression is largely restricted to thymic and peripheral CD25+ Treg Nr4a3-Timer requires a stronger and/or longer TCR signal for its expression Nr4a reporter mice are useful tools for studying TCR signaling. Jennings et al. show that Nr4a3, but not Nr4a1, is NFAT pathway dependent, resulting in restricted Nr4a3-Timer expression during T cell development. Nr4a3-Timer requires stronger and/or longer TCR signals than Nr4a1-GFP, allowing an investigation of different TCR signaling grades in vivo.
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影响因子：
16.6
作者：
Burton, Bronwen R.;Britton, Graham J.;Fang, Hai;Verhagen, Johan;Smithers, Ben;Sabatos-Peyton, Catherine A.;Carney, Laura J.;Gough, Julian;Strobel, Stephan;Wraith, David C.
通讯作者：
Wraith, David C.
DOI：
10.1073/pnas.1413726111
发表时间：
2014-09-02
影响因子：
11.1
作者：
Au-Yeung, Byron B.;Zikherman, Julie;Weiss, Arthur
通讯作者：
Weiss, Arthur
影响因子：
64.5
作者：
LIU, J;FARMER, JD;SCHREIBER, SL
通讯作者：
SCHREIBER, SL
影响因子：
32.4
作者：
Kamanaka, Masahito;Kim, Sean T.;Flavell, Richard A.
通讯作者：
Flavell, Richard A.
DOI：
10.1073/pnas.1200090109
发表时间：
2012-03-06
影响因子：
11.1
作者：
Fassett, Marlys S.;Jiang, Wenyu;Benoist, Christophe
通讯作者：
Benoist, Christophe