鱼类CD4分子研究及Treg细胞亚群鉴定分析
发布时间：2019-06-22 12:12
【摘要】：CD4是重要的淋巴细胞表面分子,在高等脊椎动物T细胞的发育和活化过程中发挥重要作用。我们从黑青斑河豚(Tetraodon nigroviridis)及斑马鱼(Daniorerio)中获得了多种CD4样(CD4-like)分子,其中包括与高等动物类似的含4个Ig结构域的CD4-4分子和鱼类特异的含2个Ig结构的CD4-2分子。与高等动物CD4分子相比,二者均具有保守的胞外Ig样结构域及胞内的酪氨酸激酶p56~(lck)结合位点。我们发现,鱼类的CD4阳性T细胞主要可以分为2类:CD4-2~-CD4-4~+和CD4-2~+CD4-4~+T细胞,且仅有后者能在促有丝分裂原刺激下增殖,并受IL-16特异性趋化。生物信息学分析发现,作为已知的高等脊椎动物CD4分子配体,IL-16和MHC-II与原始的CD4-2分子,而非CD4-4分子间更有可能存在协同进化关系。我们的研究结果提示,鱼类的CD4-2发挥了高等动物CD4的类似功能,而更有可能作为Th或Treg细胞的表面标记分子,接收外来刺激信号。 CD4~+CD25~+foxp3~+Treg细胞是一类重要的T细胞亚群,它能够诱导和维持外周免疫耐受,其功能受损与许多疾病密切相关。我们首次在低等脊椎动物中鉴定到这类细胞的存在,并从标记分子克隆、细胞表型分析、及抑制免疫活性等方面进行了分析。体外实验证明,这类细胞的缺失会引起混合淋巴细胞反应(MLR)及非特异性细胞毒效应(NCC)的显著增强;而体内移除这类细胞则会导致肠道炎症的发生。 本文的研究填补了鱼类免疫学的空白,有助于更好地认识低等脊椎动物CD4分子、调节性T细胞及它们介导的细胞调控网络,进而更全面地理解脊椎动物免疫系统的进化规律。鉴于Treg细胞在获得性免疫系统中的重要作用,鱼类Treg细胞的鉴定,不仅将为水产病害的防治提供新的策略;也为相关的临床治疗研究及药物开发提供了潜在的新模型。
[Abstract]:CD4 is an important surface molecule of lymphocytes, which plays an important role in the development and activation of T cells in higher vertebrates. A variety of CD4-like (CD4-like) molecules were obtained from puffer dolphin (Tetraodon nigroviridis) and zebrafish (Daniorerio), including CD4-4 molecules with four Ig domains and fish-specific CD4-2 molecules with two Ig structures, similar to those in higher animals. Compared with higher animal CD4 molecules, both of them have conserved extracellular Ig like domains and intracellular tyrosine kinase p56 ~ (lck) binding sites. We found that CD4 positive T cells in fish could be divided into two categories: CD4-2~-CD4-4~ and CD4-2~ CD4-4~ T cells, and only the latter could proliferate under mitogen stimulation and be specifically chemotactic by IL-16. Bioinformatics analysis showed that IL-16 and MHC-II, as known ligands of higher vertebrate CD4 molecules, were more likely to have coevolutionary relationship with original CD4-2 molecules than non-CD4-4 molecules. Our results suggest that fish CD4-2 plays a similar role in higher animal CD4 and is more likely to receive foreign stimulation signals as surface markers of Th or Treg cells. CD4~ CD25~ foxp3~ Treg cells are a kind of important T cell subsets, which can induce and maintain peripheral immune tolerance. The impairment of its function is closely related to many diseases. For the first time, we identified the existence of such cells in lower vertebrates, and analyzed them from the aspects of marker molecular cloning, phenotypic analysis and immunosuppressive activity. In vitro experiments showed that the deletion of such cells could lead to the significant increase of mixed lymphocyte reaction (MLR) and non-specific cytotoxicity (NCC), while the removal of such cells in vivo would lead to intestinal inflammation. The research in this paper fills in the gap of fish immunology and helps to better understand the CD4 molecules, regulatory T cells and their mediated cellular regulatory networks in lower vertebrates, so as to understand the evolution of vertebrate immune system more comprehensively. In view of the important role of Treg cells in acquired immune system, the identification of fish Treg cells will not only provide a new strategy for the prevention and treatment of aquatic diseases, but also provide a potential new model for related clinical treatment research and drug development.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2009
【分类号】：R392
[Abstract]:CD4 is an important surface molecule of lymphocytes, which plays an important role in the development and activation of T cells in higher vertebrates. A variety of CD4-like (CD4-like) molecules were obtained from puffer dolphin (Tetraodon nigroviridis) and zebrafish (Daniorerio), including CD4-4 molecules with four Ig domains and fish-specific CD4-2 molecules with two Ig structures, similar to those in higher animals. Compared with higher animal CD4 molecules, both of them have conserved extracellular Ig like domains and intracellular tyrosine kinase p56 ~ (lck) binding sites. We found that CD4 positive T cells in fish could be divided into two categories: CD4-2~-CD4-4~ and CD4-2~ CD4-4~ T cells, and only the latter could proliferate under mitogen stimulation and be specifically chemotactic by IL-16. Bioinformatics analysis showed that IL-16 and MHC-II, as known ligands of higher vertebrate CD4 molecules, were more likely to have coevolutionary relationship with original CD4-2 molecules than non-CD4-4 molecules. Our results suggest that fish CD4-2 plays a similar role in higher animal CD4 and is more likely to receive foreign stimulation signals as surface markers of Th or Treg cells. CD4~ CD25~ foxp3~ Treg cells are a kind of important T cell subsets, which can induce and maintain peripheral immune tolerance. The impairment of its function is closely related to many diseases. For the first time, we identified the existence of such cells in lower vertebrates, and analyzed them from the aspects of marker molecular cloning, phenotypic analysis and immunosuppressive activity. In vitro experiments showed that the deletion of such cells could lead to the significant increase of mixed lymphocyte reaction (MLR) and non-specific cytotoxicity (NCC), while the removal of such cells in vivo would lead to intestinal inflammation. The research in this paper fills in the gap of fish immunology and helps to better understand the CD4 molecules, regulatory T cells and their mediated cellular regulatory networks in lower vertebrates, so as to understand the evolution of vertebrate immune system more comprehensively. In view of the important role of Treg cells in acquired immune system, the identification of fish Treg cells will not only provide a new strategy for the prevention and treatment of aquatic diseases, but also provide a potential new model for related clinical treatment research and drug development.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2009
【分类号】：R392
【共引文献】
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