TRAF2 Deficiency in B Cells Impairs CD40-Induced Isotype Switching That Can Be Rescued by Restoring NF-κB1 Activation.
TRAF2 Deficiency in B Cells Impairs CD40-Induced Isotype Switching That Can Be Rescued by Restoring NF-κB1 Activation.
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DOI：
10.4049/jimmunol.1800337
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发表时间：
2018-12-01
期刊：
影响因子：
--
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Woolaver RA;Wang X;Dollin Y;Xie P;Wang JH;Chen Z
有效的体液免疫需要活化诱导脱氨酶（AID）催化的类别转换重组（CSR）。响应于T细胞依赖性（TD）抗原，CSR可由B细胞中的CD 40信号传导诱导。肿瘤坏死因子受体相关因子2和3（TRAF 2/TRAF 3）作为CD 40信号通路的衔接子发挥作用。先前报道了B细胞内源性TRAF 2或TRAF 3敲除小鼠（B-TRAF 2或B-TRAF 3 KO）在基因表达、B细胞存活和发育以及增大的外周淋巴器官中具有不可区分的表型。然而，目前还不清楚B-TRAF 2或B-TRAF 3的缺陷是否差异影响TD体液免疫应答和CD 40诱导的CSR。在这里，我们表明B-TRAF 2对于体内TD抗原免疫或体外接合CD 40诱导的最佳同种型转换至关重要。我们的数据澄清了B-TRAF 3的争议性作用，并证实了其在CD 40诱导的CSR中的可分配性。从机制上讲，CD 40诱导的AID表达明显受损的B-TRAF 2，但不是B-TRAF 3缺陷。此外，B-TRAF 2缺陷导致NF-κB1复合物以CD 40自主方式活化缺陷，在TRAF 2缺陷的B细胞中恢复CD 40诱导的NF-κB1活化可挽救AID表达和CSR。我们的结论是，TRAF 2是必不可少的，但TRAF 3是次要的TD体液免疫和CD 40诱导的CSR。我们的研究为通过靶向CD 40信号转导优化B细胞相关免疫疾病的治疗提供了重要的生物学基础。
Effective humoral immunity requires class switch recombination (CSR) catalyzed by activation-induced deaminase (AID). In response to T cell-dependent (TD) antigens, CSR can be induced by CD40 signaling in B cells. Tumor necrosis factor receptor associated factors 2 and 3 (TRAF2/TRAF3) function as adaptors of the CD40 signaling pathway. B cell-intrinsic TRAF2 or TRAF3 knockout mice (B-TRAF2 or B-TRAF3 KO) were previously reported to have indistinguishable phenotypes in gene expression, B cell survival and development as well as enlarged peripheral lymphoid organs. However, it remains unknown whether deficiency of B-TRAF2 or B-TRAF3 differentially affects TD humoral immune responses and CD40-induced CSR. Here, we show that B-TRAF2 is essential for optimal isotype-switching induced by in vivo TD antigen immunization or by engaging CD40 in vitro. Our data clarify the controversial role of B-TRAF3 and confirm its dispensability in CD40-induced CSR. Mechanistically, CD40-induced AID expression was markedly impaired by B-TRAF2 but not B-TRAF3 deficiency. Moreover, B-TRAF2 deficiency causes defective activation of the NF-κB1 complex in a CD40-autonomous manner, and restoring CD40-induced NF-κB1 activation in TRAF2-deficient B cells rescues AID expression and CSR. We conclude that TRAF2 is essential but TRAF3 is dispensable for TD humoral immunity and CD40-induced CSR. Our studies provide significant biological bases for optimizing treatment of B cell-associated immune disorders by targeting CD40 signaling.
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DOI：
10.4049/jimmunol.1501375
发表时间：
2015-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chen Z;Getahun A;Chen X;Dollin Y;Cambier JC;Wang JH
通讯作者：
Wang JH
影响因子：
8.1
作者：
Chen, Zhangguo;Wang, Jing H.
通讯作者：
Wang, Jing H.
影响因子：
4.8
作者：
Liao, GX;Zhang, MY;Sun, SC
通讯作者：
Sun, SC
影响因子：
4.4
作者：
Jabara, Haifa H.;Weng, Yu;Geha, Raif S.
通讯作者：
Geha, Raif S.
影响因子：
15.3
作者：
Caamano, J H;Rizzo, C A;Durham, S K;Barton, D S;Raventos-Suarez, C;Snapper, C M;Bravo, R
通讯作者：
Bravo, R