Functional, non-clonal IgMa-restricted B cell receptor interactions with the HIV-1 envelope gp41 membrane proximal external region.
Functional, non-clonal IgMa-restricted B cell receptor interactions with the HIV-1 envelope gp41 membrane proximal external region.
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DOI：
10.1371/journal.pone.0007215
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发表时间：
2009-10-06
期刊：
影响因子：
3.7
通讯作者：
Haynes BF
中科院分区：
文献类型：
--
作者：
Verkoczy L;Moody MA;Holl TM;Bouton-Verville H;Scearce RM;Hutchinson J;Alam SM;Kelsoe G;Haynes BF
HIV-1 gp 41的膜近端外部区域（MPER）具有使其成为有吸引力的基于抗体的疫苗靶点的几个特征，但是引发有效的gp 41 MPER特异性保护性抗体应答仍然是难以捉摸的。一个基本的问题是，未能制备gp 41 MPER特异性的广泛中和抗体如2F 5和4 E10是否是由于gp 41 MPER的结构限制，或者，是否gp 41 MPER表位特异性的B细胞丧失了免疫耐受性。同样重要的问题是B细胞如何与gp 41 MPER表位相互作用并对其作出应答，包括它们是否以非规范方式接合该表位，即，通过B细胞受体（BCR）的非对位识别。为了开始理解B细胞如何与gp 41 MPER结合，我们在BALB B/c和C57 BL/6小鼠中表征了B细胞-gp 41 MPER相互作用。令人惊讶的是，我们发现来自BALB/c小鼠而不是C57 BL/6小鼠的脾B细胞的显著部分（约7%）通过它们的BCR结合gp 41 MPER。这种菌株特异性结合集中在IgMhi亚群中，包括边缘区和腹膜B1 B细胞，并与体外活化的脾B细胞分泌的gp 41 MPR特异性IgM的富集级分（约15%）相关。对Igha（BALB/c）和Ighb（C57 BL/6）同源小鼠的分析表明，gp 41 MPER结合受Igha基因座的决定簇控制。MPER gp 41与IgMa相互作用的作图鉴定了与mAb 2F 5结合的MPER残基不同的MPER残基，并证明了Fc CH区的需要。重要的是，gp 41 MPER连接产生可检测的BCR近端信号传导事件，表明gp 41 MPER和IgMa决定簇之间的相互作用可能引起部分B细胞活化。这些数据表明，幼稚B细胞上gp 41 MPER和膜IG之间的低亲合力、非对位相互作用可能干扰或转移bnAb应答。
The membrane proximal external region (MPER) of HIV-1 gp41 has several features that make it an attractive antibody-based vaccine target, but eliciting an effective gp41 MPER-specific protective antibody response remains elusive. One fundamental issue is whether the failure to make gp41 MPER-specific broadly neutralizing antibodies like 2F5 and 4E10 is due to structural constraints with the gp41 MPER, or alternatively, if gp41 MPER epitope-specific B cells are lost to immunological tolerance. An equally important question is how B cells interact with, and respond to, the gp41 MPER epitope, including whether they engage this epitope in a non-canonical manner i.e., by non-paratopic recognition via B cell receptors (BCR). To begin understanding how B cells engage the gp41 MPER, we characterized B cell-gp41 MPER interactions in BALB/c and C57BL/6 mice. Surprisingly, we found that a significant (∼7%) fraction of splenic B cells from BALB/c, but not C57BL/6 mice, bound the gp41 MPER via their BCRs. This strain-specific binding was concentrated in IgMhi subsets, including marginal zone and peritoneal B1 B cells, and correlated with enriched fractions (∼15%) of gp41 MPER-specific IgM secreted by in vitro-activated splenic B cells. Analysis of Igha (BALB/c) and Ighb (C57BL/6) congenic mice demonstrated that gp41 MPER binding was controlled by determinants of the Igha locus. Mapping of MPER gp41 interactions with IgMa identified MPER residues distinct from those to which mAb 2F5 binds and demonstrated the requirement of Fc CH regions. Importantly, gp41 MPER ligation produced detectable BCR-proximal signaling events, suggesting that interactions between gp41 MPER and IgMa determinants may elicit partial B cell activation. These data suggest that low avidity, non-paratopic interactions between the gp41 MPER and membrane Ig on naïve B cells may interfere with or divert bnAb responses.
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