魚(yú)類(lèi)CD4分子研究及Treg細(xì)胞亞群鑒定分析
發(fā)布時(shí)間：2019-06-22 12:12
【摘要】：CD4是重要的淋巴細(xì)胞表面分子,在高等脊椎動(dòng)物T細(xì)胞的發(fā)育和活化過(guò)程中發(fā)揮重要作用。我們從黑青斑河豚(Tetraodon nigroviridis)及斑馬魚(yú)(Daniorerio)中獲得了多種CD4樣(CD4-like)分子,其中包括與高等動(dòng)物類(lèi)似的含4個(gè)Ig結(jié)構(gòu)域的CD4-4分子和魚(yú)類(lèi)特異的含2個(gè)Ig結(jié)構(gòu)的CD4-2分子。與高等動(dòng)物CD4分子相比,二者均具有保守的胞外Ig樣結(jié)構(gòu)域及胞內(nèi)的酪氨酸激酶p56~(lck)結(jié)合位點(diǎn)。我們發(fā)現(xiàn),魚(yú)類(lèi)的CD4陽(yáng)性T細(xì)胞主要可以分為2類(lèi):CD4-2~-CD4-4~+和CD4-2~+CD4-4~+T細(xì)胞,且僅有后者能在促有絲分裂原刺激下增殖,并受IL-16特異性趨化。生物信息學(xué)分析發(fā)現(xiàn),作為已知的高等脊椎動(dòng)物CD4分子配體,IL-16和MHC-II與原始的CD4-2分子,而非CD4-4分子間更有可能存在協(xié)同進(jìn)化關(guān)系。我們的研究結(jié)果提示,魚(yú)類(lèi)的CD4-2發(fā)揮了高等動(dòng)物CD4的類(lèi)似功能,而更有可能作為T(mén)h或Treg細(xì)胞的表面標(biāo)記分子,接收外來(lái)刺激信號(hào)。 CD4~+CD25~+foxp3~+Treg細(xì)胞是一類(lèi)重要的T細(xì)胞亞群,它能夠誘導(dǎo)和維持外周免疫耐受,其功能受損與許多疾病密切相關(guān)。我們首次在低等脊椎動(dòng)物中鑒定到這類(lèi)細(xì)胞的存在,并從標(biāo)記分子克隆、細(xì)胞表型分析、及抑制免疫活性等方面進(jìn)行了分析。體外實(shí)驗(yàn)證明,這類(lèi)細(xì)胞的缺失會(huì)引起混合淋巴細(xì)胞反應(yīng)(MLR)及非特異性細(xì)胞毒效應(yīng)(NCC)的顯著增強(qiáng);而體內(nèi)移除這類(lèi)細(xì)胞則會(huì)導(dǎo)致腸道炎癥的發(fā)生。 本文的研究填補(bǔ)了魚(yú)類(lèi)免疫學(xué)的空白,有助于更好地認(rèn)識(shí)低等脊椎動(dòng)物CD4分子、調(diào)節(jié)性T細(xì)胞及它們介導(dǎo)的細(xì)胞調(diào)控網(wǎng)絡(luò),進(jìn)而更全面地理解脊椎動(dòng)物免疫系統(tǒng)的進(jìn)化規(guī)律。鑒于Treg細(xì)胞在獲得性免疫系統(tǒng)中的重要作用,魚(yú)類(lèi)Treg細(xì)胞的鑒定,不僅將為水產(chǎn)病害的防治提供新的策略;也為相關(guān)的臨床治療研究及藥物開(kāi)發(fā)提供了潛在的新模型。
[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.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2009
【分類(lèi)號(hào)】：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.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2009
【分類(lèi)號(hào)】：R392
【共引文獻(xiàn)】
相關(guān)期刊論文 前10條
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