IL-2-mTORC1 signaling coordinates the STAT1/T-bet axis to ensure Th1 cell differentiation and anti-bacterial immune response in fish.
IL-2-mTORC1 signaling coordinates the STAT1/T-bet axis to ensure Th1 cell differentiation and anti-bacterial immune response in fish.
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DOI：
10.1371/journal.ppat.1010913
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发表时间：
2022-10
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影响因子：
6.7
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中科院分区：
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利用特化的Th 1细胞抵抗细胞内病原体感染代表了获得性免疫的重要创新。尽管转录证据表明Th 1样细胞在某些鱼类物种中的潜在存在，但这些早期脊椎动物中CD 3 + CD 4 +IFN-γ+ T细胞的存在、其详细功能以及决定其分化的机制仍不清楚。在本研究中，我们确定了一个群体的CD 3 + CD 4 -1+IFN-γ+（Th 1）细胞在尼罗罗非鱼T细胞活化在体外或爱德华氏菌感染在体内。通过去除CD 4 -1+ T细胞或阻断IFN-γ，发现Th 1细胞及其产生的IFN-γ是罗非鱼激活巨噬细胞和抵抗E.杀鱼虫感染从机制上讲，罗非鱼活化的T细胞产生IL-2，IL-2增强STAT 5和mTORC 1信号传导，进而触发STAT 1/T-bet轴控制的IFN-γ转录和Th 1细胞发育。此外，mTORC 1通过促进CD 3 + CD 4 -1+ T细胞的增殖来调节这些细胞的分化。此外，IFN-γ与其受体IFNγR1和IFNγR2结合，进一步启动STAT 1/T-bet轴介导的正反馈回路，稳定罗非鱼Th 1细胞极化。这些发现表明，在四足动物出现之前，多骨鱼尼罗罗非鱼已经进化出Th 1细胞来对抗细胞内细菌感染，并支持IL-2-mTORC 1信号协调STAT 1/T-bet轴以确定Th 1细胞命运的观点，这是一种古老的机制，在脊椎动物进化的早期就已经被编程。我们的研究有望为适应性免疫的进化提供新的视角。辅助性T（Th）细胞的分化为免疫系统提供了专门的T细胞亚群，这确保了更有效的免疫应答并减少了能量消耗，因此代表了适应性免疫的关键创新。虽然一些硬骨鱼的白细胞、CD 4 -1+淋巴细胞或CD 3 + T细胞在转录水平表达IFN-γ，表明Th 1样细胞存在于这些早期脊椎动物中，但在冷血动物中尚未鉴定出CD 3 + CD 4 -1+IFN-γ+ T细胞群。本研究证实了尼罗罗非鱼体内存在CD 3 + CD 4 -1+IFN-γ+ Th 1细胞，探讨了其在抗杀鱼爱德华氏菌感染中的免疫功能，并探讨了其分化机制。我们的研究结果表明，在出现四足动物之前，尼罗罗非鱼已经利用进化良好的Th 1细胞来对抗细胞内细菌感染，并且哺乳动物Th 1细胞分化的机制在脊椎动物进化的早期就已经被编程。
Utilization of specialized Th1 cells to resist intracellular pathogenic infection represents an important innovation of adaptive immunity. Although transcriptional evidence indicates the potential presence of Th1-like cells in some fish species, the existence of CD3+CD4+IFN-γ+ T cells, their detailed functions, and the mechanism determining their differentiation in these early vertebrates remain unclear. In the present study, we identified a population of CD3+CD4-1+IFN-γ+ (Th1) cells in Nile tilapia upon T-cell activation in vitro or Edwardsiella piscicida infection in vivo. By depleting CD4-1+ T cells or blocking IFN-γ, Th1 cells and their produced IFN-γ were found to be essential for tilapia to activate macrophages and resist the E. piscicida infection. Mechanistically, activated T cells of tilapia produce IL-2, which enhances the STAT5 and mTORC1 signaling that in turn trigger the STAT1/T-bet axis-controlled IFN-γ transcription and Th1 cell development. Additionally, mTORC1 regulates the differentiation of these cells by promoting the proliferation of CD3+CD4-1+ T cells. Moreover, IFN-γ binds to its receptors IFNγR1 and IFNγR2 and further initiates a STAT1/T-bet axis-mediated positive feedback loop to stabilize the Th1 cell polarization in tilapia. These findings demonstrate that, prior to the emergence of tetrapods, the bony fish Nile tilapia had already evolved Th1 cells to fight intracellular bacterial infection, and support the notion that IL-2–mTORC1 signaling coordinates the STAT1/T-bet axis to determine Th1 cell fate, which is an ancient mechanism that has been programmed early during vertebrate evolution. Our study is expected to provide novel perspectives into the evolution of adaptive immunity. Differentiation of T helper (Th) cells provides the immune system with specialized T-cell subsets, which ensures a more effective immune response and reduces energy expenditure, thus representing a key innovation of adaptive immunity. Although leukocytes, CD4-1+ lymphocytes, or CD3+ T cells of some bony fish have been reported to express IFN-γ at the transcriptional level, indicating that Th1-like cells exist in these early vertebrates, the CD3+CD4-1+IFN-γ+ T-cell population has not been identified in cold-blooded animals. Here, we demonstrated the existence of CD3+CD4-1+IFN-γ+ Th1 cells in Nile tilapia, explored their immunological function in resisting Edwardsiella piscicida infection, and investigated their differentiation mechanisms. Our findings suggest that prior to the emergence of tetrapods, Nile tilapia already utilized well-evolved Th1 cells to fight intracellular bacterial infection and that the mechanisms underpinning Th1 cell differentiation in mammals have been programmed early during vertebrate evolution.
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影响因子：
29.7
作者：
Boehm T;McCurley N;Sutoh Y;Schorpp M;Kasahara M;Cooper MD
通讯作者：
Cooper MD
影响因子：
3.3
作者：
Dubin, Arseny;Jorgensen, Tor Erik;Jakt, Lars Martin
通讯作者：
Jakt, Lars Martin
影响因子：
4.4
作者：
Laing, Kerry J.;Zou, Jun J.;Hansen, John D.
通讯作者：
Hansen, John D.
DOI：
10.4049/jimmunol.1600959
发表时间：
2016-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Dee CT;Nagaraju RT;Athanasiadis EI;Gray C;Fernandez Del Ama L;Johnston SA;Secombes CJ;Cvejic A;Hurlstone AF
通讯作者：
Hurlstone AF
DOI：
10.1073/pnas.2536517100
发表时间：
2003-12-09
影响因子：
11.1
作者：
Lucas, S;Ghilardi, N;de Sauvage, FJ
通讯作者：
de Sauvage, FJ