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

• Published in: The Journal of biological chemistry 2023-02, Vol.299 (2), p.102843-102843, Article 102843
• Main Authors: Zhang, Qian, Geng, Ming, Li, Kang, Gao, Haiyou, Jiao, Xinying, Ai, Kete, Wei, Xiumei, Yang, Jialong
• Format: Article
• Language: English
• Subjects: adaptive immune; Animals; Cichlids - immunology; evolution; Fish Proteins - genetics; Fish Proteins - metabolism; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp3; Gene Expression Regulation; Gene Regulatory Networks; Signal Transduction; Smad3; Smad3 Protein - genetics; Smad3 Protein - metabolism; T cell; T-Lymphocytes - immunology; teleost; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; transforming growth factor-β1
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2022.102843

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.