Protein kinase Cδ is essential for the IgG response against T-cell-independent type 2 antigens and commensal bacteria.
Protein kinase Cδ is essential for the IgG response against T-cell-independent type 2 antigens and commensal bacteria.
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DOI：
10.7554/elife.72116
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发表时间：
2021-10-25
期刊：
影响因子：
7.7
通讯作者：
Kitamura D
中科院分区：
文献类型：
--
作者：
Fukao S;Haniuda K;Tamaki H;Kitamura D
具有多价和重复结构的抗原 (Ag) 以不依赖于 T 细胞的方式引发 IgG 产生。然而，这种不依赖于 T 细胞的 2 型 (TI-2) Ag 诱导 IgG 反应的机制仍不清楚。在这里，我们报告说，B 细胞受体 (BCR) 与 TI-2 Ag 结合，但不与 T 细胞依赖性 (TD) Ag 结合，能够诱导编码激活诱导胞苷脱氨酶 (AID) 的 Aicda 转录，并在小鼠 B 细胞中与 IL-1 或 IFN-α 共刺激后，有效类别转换为 IgG3。 TI-2 Ags 强烈诱导蛋白激酶 C (PKC)δ 的磷酸化，并且 PKCδ 通过诱导 Aicda 的关键转录调节因子 BATF 介导 Aicda 转录。在 PKCδ 缺陷的小鼠中，针对 TD Ag 的 IgG 生成完整，但针对典型的 TI-2 Ag 以及共生细菌的 IgG 生成被消除，并且实验性破坏肠道上皮屏障导致致命的菌血症。因此，我们的结果揭示了 TI-2 反应中类别转换的新分子要求，并强调了其在稳态共生特异性 IgG 生产中的重要性。当人体面临潜在有害微生物时，免疫系统会通过发现并消灭病原体来做出反应。这涉及免疫系统几个不同部分的协调。 B 细胞是一种白细胞，负责产生抗体：与特定目标（例如病原体）结合的大蛋白质。 B 细胞通常需要其他免疫细胞（称为 T 细胞）的帮助才能完成抗体生成。然而，B 细胞不需要 T 细胞来产生针对某些细菌的抗体。例如，当某些涂有被称为荚膜的碳水化合物的病原菌（例如引起肺炎的肺炎球菌或沙门氏菌）侵入我们的身体时，B 细胞会使用 B 细胞抗原受体识别荚膜的重复结构。这种识别使得 B 细胞能够独立于 T 细胞产生抗体。目前尚不清楚 B 细胞在这种情况下如何产生抗体，或者这种活动需要哪些蛋白质。为了理解这个过程，Fukao 等人。使用转基因小鼠及其 B 细胞来研究它们如何独立于 T 细胞产生抗体。他们发现，一种名为 PKCδ 的蛋白质对于 B 细胞在不依赖于 T 细胞的反应中产生抗体至关重要，尤其是一种名为 IgG 的执行型抗体。当 B 细胞受到沙门氏菌或肺炎球菌等细菌表面的重复抗原刺激时，PKCδ 就会变得活跃。缺乏 PKCδ 的小鼠无法独立于 T 细胞产生 IgG，当细菌到达组织和血液时，会导致致命的感染。了解独立于 T 细胞的 B 细胞反应背后的机制可能会导致更有效的抗体产生，从而有可能为新疫苗预防由病原菌引起的致命疾病铺平道路。
Antigens (Ags) with multivalent and repetitive structure elicit IgG production in a T-cell-independent manner. However, the mechanisms by which such T-cell-independent type-2 (TI-2) Ags induce IgG responses remain obscure. Here, we report that B-cell receptor (BCR) engagement with a TI-2 Ag but not with a T-cell-dependent (TD) Ag was able to induce the transcription of Aicda encoding activation-induced cytidine deaminase (AID) and efficient class switching to IgG3 upon costimulation with IL-1 or IFN-α in mouse B cells. TI-2 Ags strongly induced the phosphorylation of protein kinase C (PKC)δ and PKCδ mediated the Aicda transcription through the induction of BATF, the key transcriptional regulator of Aicda. In PKCδ-deficient mice, production of IgG was intact against TD Ag but abrogated against typical TI-2 Ags as well as commensal bacteria, and experimental disruption of the gut epithelial barrier resulted in fatal bacteremia. Thus, our results have revealed novel molecular requirements for class switching in the TI-2 response and highlighted its importance in homeostatic commensal-specific IgG production. When the human body faces a potentially harmful microorganism, the immune system responds by finding and destroying the pathogen. This involves the coordination of several different parts of the immune system. B cells are a type of white blood cell that is responsible for producing antibodies: large proteins that bind to specific targets such as pathogens. B cells often need help from other immune cells known as T cells to complete antibody production. However, T cells are not required for B cells to produce antibodies against some bacteria. For example, when certain pathogenic bacteria coated with a carbohydrate called a capsule – such as pneumococcus, which causes pneumonia, or salmonella – invade our body, B cells recognize a repetitive structure of the capsule using a B-cell antigen receptor. This recognition allows B cells to produce antibodies independently of T cells. It is unclear how B cells produce antibodies in this situation or what proteins are required for this activity. To understand this process, Fukao et al. used genetically modified mice and their B cells to study how they produce antibodies independently of T cells. They found that a protein called PKCδ is critical for B cells to produce antibodies, especially of an executive type called IgG, in the T-cell-independent response. PKCδ became active when B cells were stimulated with the repetitive antigen present on the surface of bacteria like salmonella or pneumococcus. Mice that lack PKCδ were unable to produce IgG independently of T cells, leading to fatal infections when bacteria reached the tissues and blood. Understanding the mechanism behind the T cell-independent B cell response could lead to more effective antibody production, potentially paving the way for new vaccines to prevent fatal diseases caused by pathogenic bacteria.