Xin Gao, Hayley A McNamara, Jiwon Lee, Adrian F Lo, Deepyan Chatterjee, Dominik Spensberger, Daniel Fernandez-Ruiz, Kevin Walz, Ke Wang, Hannah G Kelly, Kai Pohl, Patricia E Carreira, Andrea Do, Le Xiong, Lynette Beattie, Alexandra J Spencer, Daniel HD Gray, Friedrich Frischknecht, Melanie Rug, Ian A. Cockburn
{"title":"以寄生虫为靶标的 B 细胞捕捉空间相连的抗原,以确保 T 细胞的帮助","authors":"Xin Gao, Hayley A McNamara, Jiwon Lee, Adrian F Lo, Deepyan Chatterjee, Dominik Spensberger, Daniel Fernandez-Ruiz, Kevin Walz, Ke Wang, Hannah G Kelly, Kai Pohl, Patricia E Carreira, Andrea Do, Le Xiong, Lynette Beattie, Alexandra J Spencer, Daniel HD Gray, Friedrich Frischknecht, Melanie Rug, Ian A. Cockburn","doi":"10.1101/2024.08.10.607257","DOIUrl":null,"url":null,"abstract":"Our understanding of T-cell-dependent humoral responses has been largely shaped by studies involving model antigens such as recombinant proteins and small viruses 1,2. In these contexts, B cells internalize the entire antigen or pathogen, to present a range of antigen to helper CD4+ T cells to initiate the humoral response. However, this model does not account for large pathogens such as parasites that are too large to be taken up by individual B cells, and the mechanisms by which B cells acquire and present antigens from large complex pathogens to T cells remain poorly understood. Here we used Plasmodium, the causative parasite of malaria, as a model to investigate the requirements for T cell help for B cells targeting the Plasmodium surface circumsporozoite protein (CSP). Upon Plasmodium sporozoite (SPZ) immunization, CSP-specific B cells can form a synapse-like structure with SPZs and take up CSP and non-CSP surface antigens. As a result, CSP-specific B cells can receive help from CD4+ T cells specific to antigens that are located on the surface but not cytosol of the Plasmodium SPZ. Therefore, B cells can obtain help, not only from T cells with the same protein specificity, but also from T cells specific for spatially linked antigens. 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引用次数: 0
摘要
我们对依赖于 T 细胞的体液反应的认识主要是通过对重组蛋白和小病毒等模型抗原的研究形成的1,2。在这些情况下,B 细胞内化整个抗原或病原体,向辅助性 CD4+ T 细胞呈现一系列抗原,从而启动体液反应。然而,这种模式无法解释寄生虫等大型病原体,因为单个 B 细胞无法吸收这些病原体,而且人们对 B 细胞从大型复杂病原体中获取并向 T 细胞呈现抗原的机制仍然知之甚少。在这里,我们以疟疾的致病寄生虫疟原虫为模型,研究了T细胞帮助B细胞靶向疟原虫表面环孢子虫蛋白(CSP)的要求。疟原虫孢子虫(SPZ)免疫后,CSP特异性B细胞可与SPZ形成突触样结构,并吸收CSP和非CSP表面抗原。因此,CSP 特异性 B 细胞可从 CD4+ T 细胞那里获得帮助,这些细胞可特异性地获得位于疟原虫 SPZ 表面而非细胞膜上的抗原。因此,B 细胞不仅能从具有相同蛋白质特异性的 T 细胞那里获得帮助,还能从对空间上相关的抗原具有特异性的 T 细胞那里获得帮助。T 细胞帮助的这种灵活性可能会增强对复杂病原体的免疫反应的启动和维持。
B cells targeting parasites capture spatially linked antigens to secure T cell help
Our understanding of T-cell-dependent humoral responses has been largely shaped by studies involving model antigens such as recombinant proteins and small viruses 1,2. In these contexts, B cells internalize the entire antigen or pathogen, to present a range of antigen to helper CD4+ T cells to initiate the humoral response. However, this model does not account for large pathogens such as parasites that are too large to be taken up by individual B cells, and the mechanisms by which B cells acquire and present antigens from large complex pathogens to T cells remain poorly understood. Here we used Plasmodium, the causative parasite of malaria, as a model to investigate the requirements for T cell help for B cells targeting the Plasmodium surface circumsporozoite protein (CSP). Upon Plasmodium sporozoite (SPZ) immunization, CSP-specific B cells can form a synapse-like structure with SPZs and take up CSP and non-CSP surface antigens. As a result, CSP-specific B cells can receive help from CD4+ T cells specific to antigens that are located on the surface but not cytosol of the Plasmodium SPZ. Therefore, B cells can obtain help, not only from T cells with the same protein specificity, but also from T cells specific for spatially linked antigens. This flexibility in T cell help, may enhance the initiation and maintenance of immune responses to complex pathogens.