Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, D-79108 Freiburg, Germany.
Nature. 2011 Feb 3;470(7332):90-4. doi: 10.1038/nature09655.
Immunologists and evolutionary biologists have been debating the nature of the immune system of jawless vertebrates--lampreys and hagfish--since the nineteenth century. In the past 50 years, these fish were shown to have antibody-like responses and the capacity to reject allografts but were found to lack the immunoglobulin-based adaptive immune system of jawed vertebrates. Recent work has shown that lampreys have lymphocytes that instead express somatically diversified antigen receptors that contain leucine-rich-repeats, termed variable lymphocyte receptors (VLRs), and that the type of VLR expressed is specific to the lymphocyte lineage: T-like lymphocytes express type A VLR (VLRA) genes, and B-like lymphocytes express VLRB genes. These clonally diverse anticipatory antigen receptors are assembled from incomplete genomic fragments by gene conversion, which is thought to be initiated by either of two genes encoding cytosine deaminase, cytosine deaminase 1 (CDA1) in T-like cells and CDA2 in B-like cells. It is unknown whether jawless fish, like jawed vertebrates, have dedicated primary lymphoid organs, such as the thymus, where the development and selection of lymphocytes takes place. Here we identify discrete thymus-like lympho-epithelial structures, termed thymoids, in the tips of the gill filaments and the neighbouring secondary lamellae (both within the gill basket) of lamprey larvae. Only in the thymoids was expression of the orthologue of the gene encoding forkhead box N1 (FOXN1), a marker of the thymopoietic microenvironment in jawed vertebrates, accompanied by expression of CDA1 and VLRA. This expression pattern was unaffected by immunization of lampreys or by stimulation with a T-cell mitogen. Non-functional VLRA gene assemblies were found frequently in the thymoids but not elsewhere, further implicating the thymoid as the site of development of T-like cells in lampreys. These findings suggest that the similarities underlying the dual nature of the adaptive immune systems in the two sister groups of vertebrates extend to primary lymphoid organs.
自 19 世纪以来,免疫学家和进化生物学家一直在争论无颚脊椎动物——七鳃鳗和盲鳗——的免疫系统的性质。在过去的 50 年里,人们发现这些鱼类具有类似抗体的反应和排斥同种异体移植物的能力,但它们缺乏有颚脊椎动物基于免疫球蛋白的适应性免疫系统。最近的研究表明,七鳃鳗的淋巴细胞表达体细胞多样化的抗原受体,这些受体含有富含亮氨酸的重复序列,称为可变淋巴细胞受体(VLR),并且表达的 VLR 类型是淋巴细胞谱系特异性的:T 样淋巴细胞表达 A 型 VLR(VLRA)基因,B 样淋巴细胞表达 VLRB 基因。这些克隆多样性的预期抗原受体是通过基因转换从不完全的基因组片段组装而成的,基因转换被认为是由编码胞嘧啶脱氨酶的两个基因之一启动的,这两个基因在 T 样细胞中编码胞嘧啶脱氨酶 1(CDA1),而在 B 样细胞中编码 CDA2。目前尚不清楚无颚鱼类是否像有颚脊椎动物一样具有专门的初级淋巴器官,如胸腺,淋巴细胞的发育和选择就在那里进行。在这里,我们在七鳃鳗幼虫的鳃丝尖端和相邻的次级薄片(都在鳃篮内)中鉴定出离散的胸腺样淋巴上皮结构,称为胸腺。只有在胸腺中,编码叉头框 N1(FOXN1)的基因的同源物才表达,FOXN1 是有颚脊椎动物胸腺生成微环境的标志物,同时还表达 CDA1 和 VLRA。这种表达模式不受七鳃鳗免疫或 T 细胞有丝分裂原刺激的影响。非功能性的 VLR 基因组装经常在胸腺中发现,但在其他地方没有发现,这进一步表明胸腺是七鳃鳗 T 样细胞发育的部位。这些发现表明,在有颚脊椎动物的两个姊妹群的适应性免疫系统的双重性质的基础上存在相似性,这种相似性延伸到初级淋巴器官。