T Cell Differentiation and Diversification in Jawless Vertebrates

无颌脊椎动物的 T 细胞分化和多样化

• 批准号: 9897541
• 负责人: Max Dale Cooper
• 金额: $ 49.07万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897541
• 关键词: Adaptive Immune System; Allogenic; Antigen Presentation; Antigen Receptors; Antigens; Cell surface; Competence; Cytidine; Deaminase; Development; Discrimination; Evolution; Family member; Gene Family; Genes; Genetic Polymorphism; Gills; Goals; Hagfish; Histocompatibility; Histocompatibility Antigens; Jaw; Lampreys; Leucine-Rich Repeat; Leukocytes; Lymphocyte; Pattern; Pilot Projects; Proteins; Receptor Gene; Role; Signal Transduction; Structure; T cell differentiation; T-Lymphocyte; Testing; Thymus Gland; Vertebrates; analog; arm; gene product; hematopoietic tissue; histocompatibility gene; insight; receptor

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.

项目摘要 提议的lamp和hag鱼的研究基于Jawless（Agnathans）和Jaw new的发现建立 （gnathostomes）脊椎动物具有原型T样和B样淋巴细胞谱系，尽管无颚 脊椎动物（七lamp和hag鱼）生成可变的淋巴细胞受体（VLR），以通过 不完整种系VLR基因（VLRA，VLRB和VLRC）的重组转化为完全 使用富含亮氨酸的Repeat（LRR）供体序列组装的VLR基因。开发分析， VLRA和VLRC淋巴细胞谱系的分布和功能表明VLRA和VLRC 谱系代表具有同种异体认知的gnathostomeα/β和γ/δT细胞的Agnathan T细胞类似物 责任。 VLRC和VLRA基因的多步组件与胞苷的表达一致 deaminase1（CDA1）在g的胸腺等效区域中，而VLRB和CDA2表达发生 令人惊讶的是，另外三个类似CDA1的基因，其产品具有 现已鉴定出脱氨酶和诱变活性。拟议的研究将定义新的 在Agnathans中发现了多基因CDA1家族成员，确定其细胞表达模式和 阐明其蛋白质产物的结构和功能。间接证据暗示VLRA 和VLRC受体依赖于相关的跨膜分子的细胞表面表达和 信号能力。本研究将确定复合受体结构和信号传导 VLRA和VLRC的能力。试点研究表明，VLRA+和VLRC+淋巴细胞优先 对同种异体白细胞反应。 VLRA和VLRC受体识别的抗原将被定义 以识别七lamp鼠组织相容性抗原并确定其在抗原中的作用的相关目标 推介会。候选组织相容性基因将检查遗传多态性，表达 模式和免疫刺激潜力测试了VLRA和VLRC认可的假设 组织相容性相关的抗原。 Agnathan组织相容性基因的识别将启发我们 关于在脊椎动物进化的关键点处自我与非自我歧视的机制。