Evolution of Diversification Mechanisms for Lymphocyte Antigen Receptors

淋巴细胞抗原受体多样化机制的进化

• 批准号: 1656870
• 负责人: Michael Criscitiello
• 金额: $ 73.93万
• 依托单位: Texas A&M AgriLife Research
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1656870&HistoricalAwards=false
• 关键词: Evolution; Diversification; Mechanisms; Lymphocyte; Antigen

Vertebrates share an adaptive immune system that is capable of great specificity in responding to pathogenic threats and a remarkable memory for previous challenges. Lymphocytes, the blood cells that mediate adaptive immunity, come in two types: B cells that secrete antibodies, and T cells that direct other immune effectors and kill infected or cancerous cells. Both B and T lymphocytes exist as vast populations in which each cell has a unique antigen receptor that is the product of DNA recombination processes. Humans have distinct genes, receptors, and diversification mechanisms that are separately employed by T cells and B cells. However, in sharks, which represent the oldest organisms with an adaptive lymphocyte system, the line between B and T lymphocytes is much blurrier. Shark B and T cells have greater plasticity to use genes, receptor modules, and receptor diversification methods that are strictly B or T lineage-specific in humans. In this project, the development of T cells in the shark will be studied in detail, including the role of a mechanism of generating mutations in these cells. The results will yield greater insight into the fundamentals of how vertebrates orchestrate adaptive immunity, in the process yielding new thinking and tools for vaccine design and immunotherapeutics. The project will contribute to STEM education through the participation of undergraduates and high school students in the research, utilizing an iterative program of teaching and hands-on research experience in collaboration with a local high school teacher.The central hypothesis of the project is that T cell receptors retain significant, ancestral, functional plasticity in the shark, evident by the organization of the antigen receptor loci, the immunogenetic processes acting upon the genes therein, development of the cells in the thymus, and the transcription profiles of the cells that express these receptors. This functional plasticity should be evident in more derived vertebrate antigen receptor diversification systems as well as in the basal shark. The central hypothesis will be tested by pursuing two aims: 1) Determine how T cells employing immunoglobulin variable genes develop in primary lymphoid tissues, diversify repertoire, are transcriptionally controlled, and whether they function more as B or T cells and 2) Identify the extent, regulation and physiological role of somatic hypermutation (SHM) at shark T cell receptor loci in both áâ and ãä T cells, and explore the boundaries of activation- induced cytidine deaminase (AID) function. The following expected outcomes are anticipated: the first aim will determine if B and T cell variable gene segments are inherently interchangeable, if the cells bearing immunoglobulin-T cell chimeric receptors develop in the thymus, if the transcriptional profile of the cells is more B- or T-like, and what they contribute to immunity. The second aim will define if thymic and peripheral SHM of T cell receptors operates for repertoire diversification, passage of thymic selection, or affinity maturation at the á and ã loci, and better define reactions catalyzed by AID.

脊椎动物都有一种适应性免疫系统，能够高度特异性地应对病原体威胁，并对之前的挑战具有非凡的记忆力。淋巴细胞是介导适应性免疫的血细胞，有两种类型：分泌抗体的 B 细胞和指导其他免疫效应器并杀死感染细胞或癌细胞的 T 细胞。 B 淋巴细胞和 T 淋巴细胞均以庞大的群体形式存在，其中每个细胞都有一个独特的抗原受体，该受体是 DNA 重组过程的产物。人类具有不同的基因、受体和多样化机制，分别由 T 细胞和 B 细胞使用。然而，在鲨鱼这种具有适应性淋巴细胞系统的最古老生物体中，B 淋巴细胞和 T 淋巴细胞之间的界限要模糊得多。鲨鱼 B 和 T 细胞具有更大的可塑性，可以使用人类 B 或 T 谱系特有的基因、受体模块和受体多样化方法。在这个项目中，将详细研究鲨鱼 T 细胞的发育，包括这些细胞中产生突变的机制的作用。这些结果将更深入地了解脊椎动物如何协调适应性免疫的基本原理，在此过程中为疫苗设计和免疫治疗提供新的思维和工具。该项目将通过本科生和高中生参与研究，利用迭代教学计划和与当地高中教师合作的实践研究经验，为 STEM 教育做出贡献。该项目的中心假设是，T 细胞受体在鲨鱼中保留了显着的、祖传的功能可塑性，这从抗原受体基因座的组织、作用于其中基因的免疫遗传过程、细胞的发育中可以看出。 胸腺中的受体，以及表达这些受体的细胞的转录谱。这种功能可塑性在更多衍生的脊椎动物抗原受体多样化系统以及基础鲨鱼中应该是明显的。将通过追求两个目标来检验中心假设：1) 确定采用免疫球蛋白可变基因的 T 细胞如何在初级淋巴组织中发育、使库多样化、受转录控制，以及它们是否更多地发挥 B 细胞或 T 细胞的功能；2) 确定 áâ 和 ãä T 细胞中鲨鱼 T 细胞受体位点体细胞超突变 (SHM) 的程度、调节和生理作用，并探索 激活诱导的胞苷脱氨酶（AID）功能的边界。预期的预期结果如下：第一个目标将确定 B 细胞和 T 细胞可变基因片段本质上是否可以互换，携带免疫球蛋白-T 细胞嵌合受体的细胞是否在胸腺中发育，细胞的转录谱是否更像 B 或 T 细胞，以及它们对免疫有何贡献。第二个目标将确定 T 细胞受体的胸腺和外周 SHM 是否对库多样化、胸腺选择通道或 á 和 ã 位点的亲和力成熟起作用，并更好地定义 AID 催化的反应。

项目成果

Conference report: The 14th congress of the International Society of Developmental and Comparative Immunology

会议报告：国际发育与比较免疫学学会第14届大会

• DOI: 10.1016/j.dci.2019.02.016
• 发表时间: 2019
• 期刊: Developmental & Comparative Immunology
• 影响因子: 2.9
• 作者: Abernath, Kelsey;Banach, Maureen;Barela Hudgell, Megan A.;Blackmon, Laura E.;Breaux, Breanna;Brusch, George A.;Criscitiello, Michael F.;Deiss, Thaddeus C.;Ding, Yang;Flowers, Emily
• 通讯作者: Flowers, Emily

Interferon epsilon and preterm birth subtypes; a new piece of the type I interferon puzzle during pregnancy?

• DOI: 10.1111/aji.13526
• 发表时间: 2022-04
• 期刊: American journal of reproductive immunology (New York, N.Y. : 1989)

Larval Thymectomy of Xenopus laevis

非洲爪蟾幼虫胸腺切除术

• DOI: 10.1101/pdb.prot099192
• 发表时间: 2018
• 期刊: Cold Spring Harbor Protocols
• 作者: Mashoof, Sara;Breaux, Breanna;Criscitiello, Michael F.
• 通讯作者: Criscitiello, Michael F.

Refining In Vitro Toxicity Models: Comparing Baseline Characteristics of Lung Cell Types

• DOI: 10.1093/toxsci/kfz001
• 发表时间: 2019-04-01
• 期刊: TOXICOLOGICAL SCIENCES
• 影响因子: 3.8
• 作者: Lujan, Henry;Criscitiello, Michael F.;Sayes, Christie M.
• 通讯作者: Sayes, Christie M.

Interferon epsilon in the reproductive tract of healthy and genital herpes simplex virus-infected pregnant women: Results of a pilot study

• DOI: 10.1111/aji.12995
• 发表时间: 2018-09-01
• 期刊: AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY
• 影响因子: 3.6
• 作者: Nickodem, Colette;Criscitiello, Michael F.;Taylor, Brandie D.
• 通讯作者: Taylor, Brandie D.