Definition of an Ancient T cell-like System in Lampreys

七鳃鳗中古代 T 细胞样系统的定义

• 批准号: 8219356
• 负责人: Max Dale Cooper
• 金额: $ 29.45万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8219356
• 关键词: Alloantigen; Allogenic; Antibodies; Antigen Receptors; Antigens; B-Lymphocytes; Binding; Cell physiology; Cells; Cellular Assay; Chimeric Proteins; Cytidine Deaminase; DNA Sequence Rearrangement; Data; Data Analyses; Detection; Development; Diagnostic Reagent; Discrimination; Elements; Engineering; Gene Expression; Gene Expression Profile; Genes; Genetic Polymorphism; Genomics; Gills; Goals; Hagfish; Hematopoietic; Histocompatibility Antigens; Immune; Immune system; Immunoglobulin Domain; Immunoglobulin Somatic Hypermutation; In Vitro; Infectious Agent; Isoantibodies; J segment gene; Jaw; Lampreys; Leucine-Rich Repeat; Leukocytes; Lymphocyte; Membrane; Modification; Molecular Profiling; Participant; Pattern; Phytohemagglutinins; Plasma Cells; Population; Receptor Gene; Receptors, Antigen, B-Cell; Recombinants; Signaling Molecule; System; T-Lymphocyte; Testing; Vertebrates; allograft rejection; analog; antigen binding; antigen processing; arm; base; cancer cell; cell type; chemokine; chemokine receptor; comparative; cytokine; design; hematopoietic tissue; histocompatibility gene; in vivo; insight; irradiation; receptor; response; skin allograft; transcription factor

DESCRIPTION (provided by applicant): The proposed studies build on the findings that interactive T- and B-like lymphocytes are basic features of the adaptive immune system of both jawless and jawed vertebrates, 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. Recent studies indicate that VLRA assembly and expression coincides with expression of cytidine deaminase 1 (CDA1) only within the lymphoepithelial thymoid gill region, whereas VLRB and CDA2 expression occurs primarily in hematopoietic tissues. A comprehensive analysis is proposed to elucidate the development, distribution and function of the lamprey VLRA and VLRC lymphocyte lineages in comparison with the B cell-like VLRB lymphocytes to test the hypothesis that the VLRA and VLRC lineages represent agnathan T cell analogues of gnathostome 1/2 and 3/4 T cells with allorecognition responsibility. A long term goal is to identify the lamprey histocompatibility antigens to test the hypothesis that VLRA and VLRC recognize these to achieve self versus non-self discrimination. The first specific aim is to define the distribution, antigen-binding and functional responses of the VLRA +, VLRB+ and VLRC+ lymphocytes and to modulate VLRA and VLRC cell function by treatment with VLR-specific antibodies to gain insight into the function and cooperative potential of the lymphocyte lineages. The second specific aim is to purify the VLRA+, VLRB+ and VLRC+ lymphocyte populations and perform a comparative analysis of each of their transcriptomes to obtain information about the differential expression of cytokines, chemokines, cytokine/chemokine receptors, cytolytic components, VLR co-receptor candidates, co-stimulatory molecules, signaling elements, and transcription factors for the three types of lymphocyte in their quiescent and activated states. The third specific aim is to characterize the allogeneic recognition and response capabilities of VLRA+, VLRB+ and VLRC+ lymphocytes. Pilot in vivo and in vitro studies indicate that the VLRA+ and VLRC+ lymphocytes preferentially respond to allogeneic white blood cells. The stimulatory cell types will be identified, the cellular participants will also be defined for skin allograft rejections, and the modulatory effects of VLRA- and VLRB-specific antibodies will be determined. Gene expression profiles and VLR sequences will be compared for alloantigen-responsive versus non-responsive lymphocytes. VLRB alloantibodies will be induced and VLRA and VLRC receptors from the alloantigen responding cells will be engineered to form secreted chimeric proteins for use in histocompatibility antigen detection. Candidate histocompatibility genes will be examined for genetic polymorphism, expression patterns and immunostimulatory potential. PUBLIC HEALTH RELEVANCE: These studies will yield insight into the basic evolutionary principles of self versus non-self recognition in vertebrates. They will also elucidate the functional interactions between the T and B cell arms of the lamprey immune system to facilitate development of lamprey VLRB antibodies for biomedical purposes by serving as unique diagnostic reagents for identifying infectious agents and cancer cells.

描述（由申请人提供）：拟议的研究基于发现的结果，即互动T和类似于淋巴结的淋巴细胞是颌骨和颌脊椎动物的自适应免疫系统的基本特征，尽管无颌骨（lampreys and hagfish）（lampreys and hagfish和hagfish）生成可变的淋巴细胞受体（VLR）良好的遗传学对抗活体认识的态度（ （VLRA，VLRB和VLRC）使用富含亮氨酸的重复（LRR）供体序列进入完全组装的VLR基因。最近的研究表明，VLRA的组装和表达与胞苷脱氨酶1（CDA1）仅在淋巴皮胸腺类g区域内的表达相吻合，而VLRB和CDA2表达主要发生在造血组织中。 与B细胞状的VLRB lymphocytes相比，提出了一项全面的分析，以阐明Lamprey VLRA和VLRC淋巴细胞谱系的发育，分布和功能，以测试VLRA和VLRC谱系的假说，即VLRA和VLRC谱系代表Gnathan T细胞责任的Agnathan T细胞类似物与gnathatostome 1/2和3/3/4 t/3/4 t/4 t/4 t/4 t/4 t t cell。 一个长期的目标是确定七lamp窃组织相容性抗原，以检验VLRA和VLRC识别这些假设以实现自我与非自我歧视的假设。 第一个具体目的是通过用VLR特异性抗体处理VLRA+，VLRB+和VLRB+和VLRC+淋巴细胞的分布，抗原结合和功能响应，并通过使用VLR特异性抗体来调节VLRA和VLRC细胞功能，以洞悉lymphopopyphopyphoppopytete的功能和合作潜力。 第二个具体目的是净化VLRA+，VLRB+和VLRC+淋巴细胞种群，并对其每个转录组进行比较分析，以获取有关细胞因子，趋化因子，细胞因子/趋化因子受体的差异表达的信息其静态和活化状态中的淋巴细胞类型。 第三个具体目的是表征VLRA+，VLRB+和VLRC+淋巴细胞的同种异体识别和响应能力。试点体内和体外研究表明，VLRA+和VLRC+淋巴细胞优先反应同种异体白细胞。 将确定刺激性细胞类型，还将定义针对皮肤同种异体拒绝的细胞参与者，并将确定VLRA和VLRB特异性抗体的调节作用。 将比较同种异体反应性与非反应性淋巴细胞的基因表达谱和VLR序列。 将诱导VLRB同种抗体，并设计来自同种抗原响应细胞的VLRA和VLRC受体，以形成分泌的嵌合蛋白，以用于组织相容性抗原检测。 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。 公共卫生相关性：这些研究将深入了解脊椎动物中自我与非自我识别的基本进化原理。 他们还将通过用作识别传染性药物和癌细胞的独特诊断试剂，阐明七lamp带免疫系统的T和B细胞臂之间的功能相互作用，以促进七lamp鼠VLRB抗体的开发。