IL-2–mTORC1 signaling coordinates the STAT1/T-bet axis to ensure Th1 cell differentiation and anti-bacterial immune response in fish

• Published in: PLoS pathogens 2022-10, Vol.18 (10), p.e1010913-e1010913
• Main Authors: Ai, Kete, Li, Kang, Jiao, Xinying, Zhang, Yu, Li, Jiaqi, Zhang, Qian, Wei, Xiumei, Yang, Jialong
• Format: Article
• Language: English
• Subjects: Adaptive immunity; Analysis; Antigens; Antiinfectives and antibacterials; Bacterial diseases; Bacterial infections; Biology and Life Sciences; CD3 antigen; CD4 antigen; Cell activation; Cell differentiation; Cell fate; Cell proliferation; Cloning; Control; Control theory; Cytokines; Differentiation (biology); Diseases; Evolution; Feedback loops; Fish; Fishes; Flow cytometry; Health aspects; Immune response; Immune system; Immunity; Immunology; Infections; Interleukin 2; Intracellular; Intracellular signalling; Lymphocytes; Lymphocytes T; Macrophages; Medicine and Health Sciences; Oreochromis niloticus; Pathogens; Physiological aspects; Population studies; Positive feedback; Proteins; Research and Analysis Methods; Signaling; Spleen; STAT1; Stat1 protein; Stat5 protein; Tilapia; Transcription factors; Vertebrates; γ-Interferon
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1010913

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.