TGF-β1 suppresses the T-cell response in teleost fish by initiating Smad3- and Foxp3-mediated transcriptional networks.
TGF-β1 suppresses the T-cell response in teleost fish by initiating Smad3- and Foxp3-mediated transcriptional networks.
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TGF-β1 通过启动 Smad3 和 Foxp3 介导的转录网络来抑制硬骨鱼中的 T 细胞反应。
DOI：
10.1016/j.jbc.2022.102843
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发表时间：
2023-02
影响因子：
4.8
通讯作者：
Yang, Jialong
中科院分区：
文献类型：
--
作者：
Zhang, Qian;Geng, Ming;Li, Kang;Gao, Haiyou;Jiao, Xinying;Ai, Kete;Wei, Xiumei;Yang, Jialong
转化生长因子-β1（Transforming growth factor-β1，TGF-β1）可抑制多种T细胞亚群的活化、增殖和功能，保护机体免受过度免疫反应引起的炎症和自身免疫性疾病的侵害。然而，TGF-β1是否以及如何在早期脊椎动物中调节T细胞免疫仍然未知。在这里，使用尼罗罗非鱼（Oreochromis niloticus）模型，我们研究了在硬骨鱼类中TGF-β1对T细胞反应的抑制。罗非鱼编码进化上保守的TGF-β1，其在杀鱼爱德华氏菌感染后的免疫应答期间在淋巴细胞中的表达被显著诱导。一旦激活，罗非鱼T细胞增加TGF-β1的产生，这反过来又抑制促炎细胞因子的表达并抑制T细胞活化。值得注意的是，我们发现施用TGF-β1削弱了罗非鱼T细胞的增殖，降低了Th 1/2分化的潜在能力，并损害了细胞毒性功能，使鱼更容易受到细菌感染。在机制上，TGF-β1启动TGF-βR/Smad信号通路并触发Smad 2/3的磷酸化和核转位。Smad 3随后与几种转录配偶体相互作用以抑制细胞因子IL-2和IFN-γ的转录，但促进免疫检查点调节因子CTLA 4和转录因子Foxp 3的转录。此外，TGF-β1/Smad信号传导进一步利用Foxp 3来实现这些T细胞基因的级联调节。综上所述，我们的研究结果揭示了TGF-β1抑制尼罗罗非鱼T细胞免疫的详细机制，并支持了TGF-β1在脊椎动物进化早期已经被用于抑制T细胞反应的观点，从而为适应性免疫系统的进化提供了新的见解。
Transforming growth factor-β1 (TGF-β1) can suppress the activation, proliferation, and function of many T-cell subsets, protecting organisms from inflammatory and autoimmune disease caused by an overexuberant immune response. However, whether and how TGF-β1 regulates T-cell immunity in early vertebrates remain unknown. Here, using a Nile tilapia (Oreochromis niloticus) model, we investigated suppression of the T-cell response by TGF-β1 in teleost species. Tilapia encodes an evolutionarily conserved TGF-β1, the expression of which in lymphocytes is significantly induced during the immune response following Edwardsiella piscicida infection. Once activated, tilapia T cells increase TGF-β1 production, which in turn suppresses proinflammatory cytokine expression and inhibits T-cell activation. Notably, we found administration of TGF-β1 cripples the proliferation of tilapia T cells, reduces the potential capacity of Th1/2 differentiation, and impairs the cytotoxic function, rendering the fish more vulnerable to bacterial infection. Mechanistically, TGF-β1 initiates the TGF-βR/Smad signaling pathway and triggers the phosphorylation and nuclear translocation of Smad2/3. Smad3 subsequently interacts with several transcriptional partners to repress transcription of cytokines IL-2 and IFN-γ but promote transcription of immune checkpoint regulator CTLA4 and transcription factor Foxp3. Furthermore, TGF-β1/Smad signaling further utilizes Foxp3 to achieve the cascade regulation of these T-cell genes. Taken together, our findings reveal a detailed mechanism by which TGF-β1 suppresses the T cell–based immunity in Nile tilapia and support the notion that TGF-β1 had already been employed to inhibit the T-cell response early in vertebrate evolution, thus providing novel insights into the evolution of the adaptive immune system.
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DOI：
10.4049/jimmunol.2100850
发表时间：
2022-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Jones BE;Maerz MD;Bahnson HT;Somasundaram A;McCarthy LH;Speake C;Buckner JH
通讯作者：
Buckner JH
DOI：
10.1002/dvdy.423
发表时间：
2022-01
期刊：
Developmental dynamics : an official publication of the American Association of Anatomists
影响因子：
--
作者：
Goodman MB;Savage-Dunn C
通讯作者：
Savage-Dunn C
影响因子：
32.4
作者：
Gorelik, L;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
6.7
作者：
通讯作者：
--
从受体到 Smads 的 TGF-β 信号传导
影响因子：
7.2
作者：
Hata A;Chen YG
通讯作者：
Chen YG