Yilmaz Erdem, Rahimi Amirmohammad, Münchhalfen Matthias, Alevra Mihai, Golmohammadi Arash, Tetzlaff Christian, Opazo Felipe, Engels Niklas
Institute of Cellular & Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany.
Center for Biostructural Imaging of Neurodegeneration (BIN), University Medical Center Göttingen, Göttingen, Germany.
Cell Mol Immunol. 2025 Aug 6. doi: 10.1038/s41423-025-01327-1.
Antibodies, also known as immunoglobulins, share an evolutionarily conserved dimeric core structure with two antigen binding sites. However, recognition of foreign molecules can be achieved by monovalent binding domains, as evidenced by the T-cell antigen receptor and various innate immune receptors. Thus, the reason for the strict evolutionary conservation of immunoglobulin divalence remains unclear. In addition to being soluble immune effector molecules, each immunoglobulin is also expressed as a membrane-bound isoform in the context of the B-cell antigen receptor (BCR). Here, we generated monovalent BCRs and found that their signaling and antigen internalization capabilities were strongly impaired. By using advanced superresolution imaging of BCRs following stimulation with antigens of distinct valences, we showed that the receptor cluster scale in the plasma membrane determines the magnitude of intracellular signaling. The incorporation of additional ITAMs into single BCRs did not increase receptor sensitivity but caused cellular desensitization. Our results demonstrate that the BCR-controlled signaling machinery senses the clustering status of the BCR and that subtle changes in cluster sizes are translated into cellular responses. These findings improve our knowledge of adaptive immune receptor function and will aid in the design of synthetic chimeric antigen receptors.
抗体，也被称为免疫球蛋白，与两个抗原结合位点共享一个进化上保守的二聚体核心结构。然而，如T细胞抗原受体和各种先天免疫受体所示，通过单价结合域也能够实现对外源分子的识别。因此，免疫球蛋白二价性严格进化保守的原因仍不清楚。除了作为可溶性免疫效应分子外，每种免疫球蛋白在B细胞抗原受体（BCR）的背景下也以膜结合异构体的形式表达。在此，我们生成了单价BCR，并发现它们的信号传导和抗原内化能力严重受损。通过对不同价态抗原刺激后的BCR进行先进的超分辨率成像，我们表明质膜中的受体簇规模决定了细胞内信号传导的强度。将额外的免疫受体酪氨酸激活基序（ITAM）掺入单个BCR中并不会增加受体敏感性，反而会导致细胞脱敏。我们的结果表明，BCR控制的信号传导机制能够感知BCR的聚集状态，并且簇大小的细微变化会转化为细胞反应。这些发现增进了我们对适应性免疫受体功能的了解，并将有助于合成嵌合抗原受体的设计。
