Full T-cell activation and function in teleosts require collaboration of first and co-stimulatory signals
Wei Liang, 华东师范大学生命科学学院河口海岸国家重点实验室, 上海 200241, 中国, Kang Li, Haiyou Gao, Kunming Li, Jiansong Zhang, Qian Zhang, Xinying Jiao, Jialong Yang, Xiumei Wei, 青岛海洋科学与技术国家实验室, 海洋生物与技术实验室, 山东 青岛 266237, 中国
Abstract
T cells response in mammals requires synergism of the first signal and co-stimulatory signal. However, whether and how dual signaling regulates the T-cell response in early vertebrates remains unknown. In present study, we found that the teleost Nile tilapia Oreochromis niloticus encodes the key components of LAT signalosome: LAT, ITK, GRB2, VAV1, SLP-76, GADS, and PLC-γ1. These components are evolutionarily conserved, and CD3ε mAb-induced T-cell activation markedly increased their expression; while at least ITK, GRB2, and VAV1 could interact with LAT to form the signalosome. Downstream of the first signal, the NF-κB, MAPK/Erk, and PI3K-AKT pathways were activated upon CD3ε mAb stimulation. Furthermore, treatment of lymphocytes with CD28 mAbs triggered the AKT-mTORC1 pathway downstream of the co-stimulatory signal. A combined stimulation using CD3ε plus CD28 mAbs enhanced the phosphorylation of Erk1/2 and S6 and elevated the expression of NFAT1, c-Fos, IL-2, CD122, and CD44, signifying T-cell activation. Moreover, instead of the first signal or co-stimulatory signal alone, both dual signals are required for T-cell proliferation. In addition, full T-cell activation was accompanied by marked apoptosis and cytotoxic response. Therefore, our findings suggest that tilapia relies on dual signaling to maintain the optimal T-cell response, providing a novel perspective for understanding the evolution of the adaptive immune system.