TGF-β1 suppresses the T-cell response in teleost fish by initiating Smad3-and Foxp3-mediated transcriptional networks

作者：Zhang, Qian; Geng, Ming; Li, Kang; Gao, Haiyou; Jiao, Xinying; Ai, Kete; Wei, Xiumei^*; Yang, Jialong^*

来源：Journal of Biological Chemistry, 2023, 299(2): 102843.

DOI：10.1016/j.jbc.2022.102843

• GROWTH-FACTOR-BETA
• INFLAMMATORY RESPONSE
• EXPRESSION ANALYSIS
• MOLECULAR-CLONING
• PERIPHERAL-BLOOD
• FOXP3 EXPRESSION
• ACTIVATION
• IMMUNITY
• IL-10
• INTERLEUKIN-10

Transforming growth factor -81 (TGF-81) 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. How-ever, whether and how TGF-81 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-81 in teleost species. Tilapia en-codes an evolutionarily conserved TGF-81, the expression of which in lymphocytes is significantly induced during the im-mune response following Edwardsiella piscicida infection. Once activated, tilapia T cells increase TGF-81 production, which in turn suppresses proinflammatory cytokine expression and inhibits T-cell activation. Notably, we found administra-tion of TGF-81 cripples the proliferation of tilapia T cells, re-duces the potential capacity of Th1/2 differentiation, and impairs the cytotoxic function, rendering the fish more vulnerable to bacterial infection. Mechanistically, TGF-81 ini-tiates the TGF-8R/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-y but promote transcription of immune checkpoint regulator CTLA4 and transcription factor Foxp3. Furthermore, TGF-81/Smad signaling further utilizes Foxp3 to achieve the cascade regula-tion of these T-cell genes. Taken together, our findings reveal a detailed mechanism by which TGF-81 suppresses the T cell- based immunity in Nile tilapia and support the notion that TGF-81 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.