T Cell Differentiation and Diversification in Jawless Vertebrates

项目摘要 对七鳃鳗和八目鳗的拟议研究建立在无颌类和有颌类的发现之上。 （有颌类）脊椎动物有原型T样和B样淋巴细胞谱系，虽然无颌 脊椎动物（七鳃鳗和八目鳗）产生用于抗原识别的可变淋巴细胞受体（VLR）， 将不完全生殖系VLR基因（VLRA、VLRB和VLRC）重组转化为完全生殖系VLR基因（VLRA、VLRB和VLRC）。 使用不同的富含亮氨酸重复序列（LRR）供体序列组装VLR基因。发展分析， VLRA和VLRC淋巴细胞谱系的分布和功能表明，VLRA和VLRC淋巴细胞谱系的分布和功能可能与VLRA和VLRC淋巴细胞谱系的分布和功能有关。 谱系代表了具有同种识别能力的颚口α/β和γ/δ T细胞的无颌T细胞类似物 责任VLRC和VLRA基因的多步组装与胞苷的表达一致 脱氨酶1（CDA 1）在胸腺相当于区域的鳃，而VLRB和CDA 2的表达发生 主要在造血组织中。令人惊讶的是，三个额外的CDA 1样基因，其产物具有 脱氨酶和致突变活性，现已确定。拟议的研究将界定新的 在无颌症中发现多基因CDA 1家族成员，确定其细胞表达模式， 阐明其蛋白质产物的结构和功能。间接证据表明VLRA 和VLRC受体依赖于相关的跨膜分子用于它们的细胞表面表达， 信号能力目前的研究将确定复合受体的结构和信号转导 VLRA和VLRC的能力。初步研究表明，VLRA+和VLRC+淋巴细胞优先 对同种异体白色血细胞有反应。将定义VLRA和VLRC受体识别的抗原 相关目的是鉴定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.将检查候选组织相容性基因的遗传多态性、表达 模式和免疫刺激潜力，以检验VLRA和VLRC识别 组织相容性相关抗原。无颌类组织相容性基因的鉴定将给我们以启示 在脊椎动物进化的关键时刻，自我与非自我的区别机制。

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.