Interleukin (IL)-2 Is a Key Regulator of T Helper 1 and T Helper 2 Cytokine Expression in Fish: Functional Characterization of Two Divergent IL2 Paralogs in Salmonids.
Interleukin (IL)-2 Is a Key Regulator of T Helper 1 and T Helper 2 Cytokine Expression in Fish: Functional Characterization of Two Divergent IL2 Paralogs in Salmonids.
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白介素（IL）-2是T辅助器1和T辅助2细胞因子表达的关键调节剂：鲑鱼中两个发散IL2旁系同源物的功能表征。
DOI：
10.3389/fimmu.2018.01683
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发表时间：
2018
影响因子：
7.3
通讯作者：
Secombes CJ
中科院分区：
文献类型：
--
作者：
Wang T;Hu Y;Wangkahart E;Liu F;Wang A;Zahran E;Maisey KR;Liu M;Xu Q;Imarai M;Secombes CJ
哺乳动物白细胞介素(IL)-2是一种细胞因子，主要参与CD4+ T辅助亚群和CD4+ T调节细胞的分化和存活，以及细胞毒性效应淋巴细胞的激活。在硬骨鱼中，已经鉴定出在几种鱼类中存在的同一位点上有一个额外的不同的IL2样基因。我们在这里报告了两个不同的IL2类似物，IL2A和IL2B，在鲑鱼中起源于该鱼类谱系的全基因组复制事件。鲑鱼的IL2相似物不仅在序列上不同，而且在外显子大小上也不同。被编码的IL-2亚型具有不同的pI值，可能已经进化到优先结合特定的IL-2受体。虹鳟鱼的il - 2类似物在胸腺、脾脏、鳃、肾脏和肠道中高度表达，是鱼类T细胞发育和功能的重要组织/器官。它们在外周血白细胞（PBL）中的表达水平较低，但可通过混合白细胞反应、T细胞有丝分裂原植物血凝素和T细胞激活的信号模拟物（12-肉豆蔻酸13-乙酸磷和钙离子载体）上调。这两种IL-2亚型均能促进PBL增殖，并维持CD4和CD8的高水平表达，表明鳟鱼IL-2亚型是主要由活化的T细胞表达的T细胞生长/存活因子。这两种鳟鱼il - 2类似物的重组蛋白已在大肠杆菌中产生，并具有相同但不同的生物活性。IL-2A而非IL-2B诱导PBL中IL12P35A1和CXCR1的表达。IL-2B对T辅助1 （Th1）细胞因子干扰素-γ (IFNγ)的上调有较强的作用，并能维持CD8α和CD8β的表达水平。然而，这两种细胞因子上调了关键的Th1 （IFNγ1、IFNγ2、TNFα2和IL12）和T辅助2 （Th2）细胞因子（IL4/13B1和IL4/13B2）、细胞因子和趋化因子受体以及抗菌肽cathelicidin-1，但对PBL中T辅助17细胞因子和TGFβ1的影响有限。它们还能增强PBL的吞噬作用。这些结果首次在鱼类中表明，IL-2亚型可能在调节鱼类Th1和Th2细胞发育以及先天和适应性宿主防御中发挥重要作用，并揭示了IL-2在脊椎动物中的谱系特异性扩增、进化和功能多样化。
Mammalian interleukin (IL)-2 is a cytokine centrally involved in the differentiation and survival of CD4+ T helper subsets and CD4+ T regulatory cells and in activation of cytotoxic effector lymphocytes. In bony fish, IL2 orthologs have been identified with an additional divergent IL2-Like gene on the same locus present in several fish species. We report here two divergent IL2 paralogs, IL2A and IL2B, in salmonids that originated from the whole genome duplication event in this fish lineage. The salmonid IL2 paralogs differ not only in sequence but also in exon sizes. The IL-2 isoforms that are encoded have disparate pI values and may have evolved to preferentially bind specific IL-2 receptors. Rainbow trout IL2 paralogs are highly expressed in thymus, spleen, gills, kidney and intestine, important tissues/organs in fish T cell development and function. Their expression in peripheral blood leukocytes (PBL) is low constitutively but can be upregulated by the mixed leukocyte reaction, by the T cell mitogen phytohemagglutinin and by signal mimics of T cell activation (phorbol 12-myristate 13-acetate and calcium ionophore). Both trout IL-2 isoforms promoted PBL proliferation and sustained high-level expression of CD4 and CD8, suggesting that trout IL-2 isoforms are T cell growth/survival factors mainly expressed by activated T cells. The recombinant proteins for these two trout IL2 paralogs have been produced in E. coli and possess shared but also distinct bioactivities. IL-2A, but not IL-2B, induced IL12P35A1 and CXCR1 expression in PBL. IL-2B had a stronger effect on upregulation of the T helper 1 (Th1) cytokine interferon-γ (IFNγ) and could sustain CD8α and CD8β expression levels. Nevertheless, both cytokines upregulated key Th1 (IFNγ1, IFNγ2, TNFα2 and IL12) and T helper 2 (Th2) cytokines (IL4/13B1 and IL4/13B2), cytokine and chemokine receptors and the antimicrobial peptide cathelicidin-1 but had limited effects on T helper 17 cytokines and TGFβ1 in PBL. They could also enhance PBL phagocytosis. These results suggest, for the first time in fish, that IL-2 isoforms may have an important role in regulating Th1 and Th2 cell development, and innate and adaptive host defenses in fish, and shed light on lineage-specific expansion, evolution, and functional diversification of IL2 in vertebrates.
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