BCR and Endosomal TLR Signals Synergize to Increase AID Expression and Establish Central B Cell Tolerance.
BCR and Endosomal TLR Signals Synergize to Increase AID Expression and Establish Central B Cell Tolerance.
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DOI：
10.1016/j.celrep.2017.01.050
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发表时间：
2017-02-14
期刊：
影响因子：
8.8
通讯作者：
Kelsoe G
中科院分区：
文献类型：
--
作者：
Kuraoka M;Snowden PB;Nojima T;Verkoczy L;Haynes BF;Kitamura D;Kelsoe G
激活诱导的胞苷脱氨酶（AID）需要在第一个耐受检查点清除自身反应性未成熟和过渡期-1（未成熟/T1）B细胞，但AID如何选择性地去除自身反应性B细胞尚不清楚。我们现在发现，B细胞抗原受体（BCR）和内体Toll样受体（TLR）信号协同作用，在未成熟/T1 B细胞中引起高水平的AID表达。这种协同作用仅限于内吞TLR的配体，并且需要磷脂酶-D活化、内体酸化和MyD 88。第一个检查点在AID或MyD 88缺陷小鼠和AID和MyD 88双杂合子小鼠中显著受损，表明这些因子在中枢B细胞耐受性中的相互作用。此外，氯喹，一种内体酸化的抑制剂，给药导致不能去除小鼠中的自身反应性未成熟/T1 B细胞。我们认为BCR/TLR途径通过过度激活结合内体TLR配体的未成熟/T1 B细胞中的AID来协调建立中枢耐受。BCR和MyD 88信号协同作用，使自身反应性未成熟和过渡期B细胞中AID表达显著增加，并介导其通过凋亡而丧失。
Activation-induced cytidine deaminase (AID) is required to purge autoreactive immature and transitional-1 (immature/T1) B cells at the first tolerance checkpoint but how AID selectively removes self-reactive B cells is unclear. We now show that B cell antigen receptor (BCR) and endosomal Toll-like receptor (TLR) signals synergize to elicit high levels of AID expression in immature/T1 B cells. This synergy is restricted to ligands for endocytic TLR and requires phospholipase-D activation, endosomal acidification, and MyD88. The first checkpoint is significantly impaired in AID- or MyD88-deficient mice and in mice doubly heterozygous for AID and MyD88, suggesting interaction of these factors in central B cell tolerance. Moreover, administration of chloroquine, an inhibitor of endosomal acidification, results in a failure to remove autoreactive immature/T1 B cells in mice. We propose that a BCR/TLR pathway coordinately establishes central tolerance by hyper-activating AID in immature/T1 B cells that bind ligands for endosomal TLRs. BCR and MyD88 signals synergize to increase AID expression greatly in autoreactive immature and transitional B cells and to mediate their loss by apoptosis.