Evolution of Adaptive Immunity

摘要 对非哺乳动物脊椎动物(鱼、两栖动物、爬行动物和鸟类)的研究提供了 获得性免疫的基本发现，特别是关于淋巴细胞谱系，起源 主要组织相容性复合体(MHC)、粘膜免疫和抗原受体。从… 我们在鲨鱼身上所做的工作，鲨鱼是最古老的脊椎动物，具有免疫球蛋白，T细胞 受体和MHC，我们假设哺乳动物B1细胞范式可以在 新生和幼年动物。鲨鱼也有结合位点不变的抗体(生殖系- 联合基因编码抗体)，这些抗体在分泌型B细胞中表达，但在幼稚B细胞中不表达 细胞。抗体被模拟成有一个不寻常的结合部位，它结合到自己的组织和 细菌，它被认为是哺乳动物中B1衍生抗体的模型。一秒钟 鲨鱼B细胞具有独特的免疫球蛋白谱(也是类B1，N区很少)的波 此外)形成新生的脾白髓，也被提议为所有人的范例 脊椎动物，我们将在老鼠和两栖动物身上进行测试。关于体液免疫反应， 众所周知，非哺乳动物脊椎动物的抗体亲和力较差，成熟程度较低。 而且似乎缺乏滤泡树突状细胞(FDC)；因此其机制如何自然 抗原被提呈给B细胞的情况还知之甚少。我们重新鉴定了一种呈现抗原的 青蛙细胞(APC)，表达高水平的MHC-II类，但仍提供天然抗原 免疫后较晚在B细胞滤泡中心的表面。我们假设 这些抗原前体细胞具有“双重功能”，将抗原递呈给T细胞和B细胞。我们的数据 提示T细胞在反应早期被这些APC刺激，然后被激活的T细胞 细胞许可APC停止降解抗原，上调B细胞趋化因子(CXCL13)，以及 进入卵泡，将抗原呈递给特定的B细胞。我们假设这个细胞代表 冷血脊椎动物体液反应的范例，以及传统的 哺乳动物树突状细胞可以呈现这种“双重功能”表型，特别是免疫反应。

SUMMARY Studies of nonmammalian vertebrates (fish, amphibians, reptiles, and birds) have provided essential discoveries in adaptive immunity, especially regarding lymphocyte lineages, origins of the major histocompatibility complex (MHC), mucosal immunity, and antigen receptors. From work that we have done in sharks, the oldest living vertebrates with immunoglobulins, T cell receptors and the MHC, we hypothesize that the mammalian B1 cell paradigm is operable in neonatal and young animals. Sharks also have antibodies with invariant binding sites (germline- joined gene-encoded antibodies), which are expressed in secretory B cells but not in naïve B cells. The antibody is modeled to have an unusual binding site, it binds to self tissues and bacteria, and it is proposed to be a model for B1-derived antibodies in mammals. A second wave of shark B cells with a unique immunoglobulin repertoire (also B1-like, with little N-region addition) forms the nascent splenic white pulp, also proposed to be the paradigm for all vertebrates, which we will test in mice and amphibians. Regarding humoral immune responses, it is well known that nonmammalian vertebrates have poor affinity maturation of the antibody response and seem to lack follicular dendritic cells (FDC); thus the mechanism of how native antigen is presented to B cells is poorly understood. We have re-identified an antigen presenting cell (APC) in frogs that expresses high levels of MHC class II, and yet presents native antigen on its surface in the center of B cell follicles relatively late after immunization. We hypothesize that these APC perform a `double-duty,' presenting antigen to both T cells and B cells. Our data suggest that T cells are stimulated by these APC early in a response, and then the activated T cells license the APC to stop degrading antigen, upregulate B cell chemokines (cxcl13), and enter the follicle to present antigen to specific B cells. We hypothesize that this cell represents the paradigm for humoral responses in cold-blooded vertebrates, and that conventional mammalian DC can take on this `double-duty' phenotype in particular immune responses.