TGF-ß1 suppresses the T-cell response in teleost fish by initiating Smad3- and Foxp3-mediated transcriptional networks.
J Biol Chem
; 299(2): 102843, 2023 02.
Article
de En
| MEDLINE
| ID: mdl-36581209
ABSTRACT
Transforming growth factor-ß1 (TGF-ß1) 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-ß1 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-ß1 in teleost species. Tilapia encodes an evolutionarily conserved TGF-ß1, the expression of which in lymphocytes is significantly induced during the immune response following Edwardsiella piscicida infection. Once activated, tilapia T cells increase TGF-ß1 production, which in turn suppresses proinflammatory cytokine expression and inhibits T-cell activation. Notably, we found administration of TGF-ß1 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-ß1 initiates the TGF-ßR/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-ß1/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-ß1 suppresses the T cell-based immunity in Nile tilapia and support the notion that TGF-ß1 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.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Lymphocytes T
/
Cichlides
/
Protéine Smad-3
/
Facteurs de transcription Forkhead
/
Facteur de croissance transformant bêta-1
Type d'étude:
Prognostic_studies
Limites:
Animals
Langue:
En
Journal:
J Biol Chem
Année:
2023
Type de document:
Article
Pays d'affiliation:
Chine