T Cell Differentiation and Diversification in Jawless Vertebrates

项目总结 拟议中的七鳃鳗和七鳃鳗的研究建立在无下颌和有下颌的研究结果的基础上 脊椎动物虽然没有颌骨，但有典型的T样和B样淋巴细胞谱系 脊椎动物(七鳃鳗和七鳃鳗)通过以下方式产生可识别抗原的可变淋巴细胞受体(VLR) 不完全胚系VLR基因(VLRA、VLRB和VLRC)的重组转化 使用不同的富亮氨酸重复序列(LRR)供体序列组装VLR基因。对发展的分析， VLRA和VLRC淋巴细胞谱系的分布和功能提示VLRA和VLRC 谱系代表具有同种异体识别功能的α/β和γ/δT细胞的无核T细胞类似物 责任。VLRC和VLRA基因的多步组装与胞苷的表达相一致 在鳃的胸腺等效区表达脱氨酶1(CDA1)，而VLRB和CDA2表达 主要是在造血组织中。令人惊讶的是，另外三个类似CDA1的基因，其产物具有 脱氨酶和致突变活性，现在已经确定。拟议的研究将定义新的 在无脊椎动物中发现多基因CDA1家族成员，确定其细胞表达模式，并 阐明它们的蛋白质产物的结构和功能。间接证据表明，VLRA 而VLRC受体依赖于相关的跨膜分子来表达细胞表面和 信号传递能力。目前的研究将确定复合受体的结构和信号转导 具备VLRA和VLRC的能力。初步研究表明，VLRA和VLRC淋巴细胞优先 对同种异体白细胞有反应。VLRA和VLRC受体识别的抗原将被定义 相关的目标是识别七鳃鳗组织相容性抗原并确定它们在抗原中的作用 演示文稿。将对候选组织相容性基因进行遗传多态、表达 验证VLRA和VLRC识别假说的模式和免疫刺激潜力 组织相容性相关抗原。组织亲和性基因的鉴定将给我们带来启示 关于在脊椎动物进化的关键时刻自我与非自我区别的机制。

PROJECT SUMMARY The proposed studies in lampreys and hagfish build on the findings that both jawless (agnathans) and jawed (gnathostomes) vertebrates have prototypic T-like and B-like lymphocyte lineages, although jawless vertebrates (lampreys and hagfish) generate variable lymphocyte receptors (VLR) for antigen recognition by recombinatorial conversion of incomplete germline VLR genes (VLRA, VLRB and VLRC) into fully assembled VLR genes using diverse leucine-rich-repeat (LRR) donor sequences. Analysis of the development, distribution and function of the VLRA and VLRC lymphocyte lineages suggest that the VLRA and VLRC lineages represent the agnathan T cell analogues of gnathostome α/β and γ/δ T cells with allorecognition responsibility. The multistep assembly of VLRC and VLRA genes coincides with expression of cytidine deaminase1 (CDA1) in a thymus-equivalent region of the gills, whereas VLRB and CDA2 expression occurs primarily in hematopoietic tissues. Surprisingly, three additional CDA1-like genes, the products of which have deaminase and mutagenic activity, have now been identified. The proposed studies will define the newly discovered multigene CDA1 family members in agnathans, determine their cellular expression patterns and elucidate the structure and functions of their protein products. Circumstantial evidence implies that the VLRA and VLRC receptors rely on associated transmembrane molecules for their cell surface expression and signaling competence. The present studies will determine the composite receptor structure and signaling competence for VLRA and VLRC. Pilot studies indicate that the VLRA+ and VLRC+ lymphocytes preferentially respond to allogeneic white blood cells. The antigens recognized by VLRA and VLRC receptors will be defined with the related goal of identifying lamprey histocompatibility antigens and determining their roles in antigen presentation. Candidate histocompatibility genes will be examined for genetic polymorphism, expression patterns and immunostimulatory potential to test the hypothesis that VLRA and VLRC recognize histocompatibility-associated antigens. Identification of the agnathan histocompatibility genes will enlighten us about the mechanisms of self versus non-self discrimination at a pivotal juncture of vertebrate evolution.