NDRG1 is induced by antigen-receptor signaling but dispensable for B and T cell self-tolerance.
NDRG1 is induced by antigen-receptor signaling but dispensable for B and T cell self-tolerance.
复制标题
DOI：
10.1038/s42003-022-04118-w
复制
发表时间：
2022-11-10
影响因子：
5.9
通讯作者：
中科院分区：
文献类型：
--
作者：
外周耐受防止自身反应性淋巴细胞引发破坏性免疫应答。虽然致耐受性机制受到抗原依赖性和非依赖性信号的严格调节，但下游途径尚未完全了解。N-myc下游调节基因1（NDRG1）是一个抗癌治疗靶点，以前被认为是CD4 + T细胞克隆性无能因子。通过RNA测序，我们鉴定出Ndrg 1是无反应性的第三大上调基因，与幼稚的滤泡B细胞相比。NDRG 1被B细胞受体激活（信号一）上调，并被共刺激（信号二）抑制，这表明NDRG 1可能在B细胞耐受中很重要。然而，尽管NDRG 1 −/−小鼠具有类似NDRG 1相关Charcot-Marie-Tooth（CMT4d）疾病的神经缺陷，但原发性和继发性免疫反应是正常的。我们发现，B细胞耐受性得以维持，NDRG 1在体内抗原经历的CD4 + T细胞再刺激过程中的下游反应中不起作用，表明NDGR 1在淋巴细胞无反应性方面是功能冗余的。尽管在无变应性B细胞中上调，但N-myc下游调节基因1（NDRG 1）对于致耐受性下游应答不是必需的，从而降低了针对癌症治疗的NDRG 1靶向的免疫调节的风险。
Peripheral tolerance prevents the initiation of damaging immune responses by autoreactive lymphocytes. While tolerogenic mechanisms are tightly regulated by antigen-dependent and independent signals, downstream pathways are incompletely understood. N-myc downstream-regulated gene 1 (NDRG1), an anti-cancer therapeutic target, has previously been implicated as a CD4+ T cell clonal anergy factor. By RNA-sequencing, we identified Ndrg1 as the third most upregulated gene in anergic, compared to naïve follicular, B cells. Ndrg1 is upregulated by B cell receptor activation (signal one) and suppressed by co-stimulation (signal two), suggesting that NDRG1 may be important in B cell tolerance. However, though Ndrg1−/− mice have a neurological defect mimicking NDRG1-associated Charcot-Marie-Tooth (CMT4d) disease, primary and secondary immune responses were normal. We find that B cell tolerance is maintained, and NDRG1 does not play a role in downstream responses during re-stimulation of in vivo antigen-experienced CD4+ T cells, demonstrating that NDGR1 is functionally redundant for lymphocyte anergy. Despite an upregulation in anergic B cells, N-myc downstream-regulated gene 1 (NDRG1) is not required for the tolerogenic downstream responses, reducing risk of immune modulation on targeting of NDRG1 for cancer therapeutics.
登录
查看更多内容
DOI：
10.1084/jem.179.2.425
发表时间：
1994-02-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cooke MP;Heath AW;Shokat KM;Zeng Y;Finkelman FD;Linsley PS;Howard M;Goodnow CC
通讯作者：
Goodnow CC
影响因子：
2.8
作者：
Echaniz-Laguna, Andoni;Degos, Bertrand;Leheup, Bruno
通讯作者：
Leheup, Bruno
影响因子：
7.5
作者：
Chua, Mei-Sze;Sun, Hongbo;So, Samuel
通讯作者：
So, Samuel
影响因子：
6.2
作者：
Chen, Jianquan;Holguin, Nilsson;Shi, Yu;Silva, Matthew J.;Long, Fanxin
通讯作者：
Long, Fanxin
B细胞受体进入信号传导结构域被抑制在耐受的B细胞中。
影响因子：
15.3
作者：
Weintraub, B C;Jun, J E;Bishop, A C;Shokat, K M;Thomas, M L;Goodnow, C C
通讯作者：
Goodnow, C C