Akt1/mTORC1 signaling modulates adaptive immune response of Nile tilapia by promoting lymphocyte activation and proliferation

Serving as a significant signaling molecule, RAC-alpha serine/threonine-protein kinase (Akt1) plays indispensable roles in cell cycle, growth, survival, metabolism, as well as immune response. However, how Akt1 regulates adaptive immune response in early vertebrate, especially the teleost, is largely unknown. Here, using a Nile tilapia Oreochromis niloticus model, we investigated the regulatory role of Akt1 in adaptive immunity of teleost. Both sequence and structure of the O. niloticus Akt1 (OnAkt1), were evolutionarily conserved comparing with the counterparts from other vertebrates. mRNA of OnAkt1 was widely expressed in lymphoid organs/tissues of Nile tilapia, with relative higher level in PBL. After Nile tilapia was infected by Aeromonas hydrophila, both transcription and phosphorylation levels of OnAkt1 were obviously elevated in spleen lymphocytes at the adaptive immune stage, suggesting Akt1 participated in primary adaptive immune response of Nile tilapia. Furthermore, OnAkt1 transcript or phosphorylation was dramatically augmented after spleen lymphocytes were activated by T cell specific mitogen PHA or lymphocyte agonist PMA. More critically, inhibition of Akt1 by specific inhibitor crippled the activation of downstream mTORC1 signaling, and impaired the up-regulation of T cell activation markers CD44, IFN-γ and CD122 in spleen lymphocytes upon PHA-induced T cell activation. Meanwhile, blockade of Akt1-activated mTORC1 signaling also decreased the frequency of BrdU⁺ lymphocytes during A. hydrophila Infection, indicating the critical role of Akt1 in regulating lymphocyte proliferation of Nile tilapia. Together, our results demonstrated that Akt1 modulated adaptive immune response of Nile tilapia by promoting lymphocyte activation and proliferation via mTORC1 signaling. Our study enriched the regulatory mechanism of lymphocyte-mediated adaptive immunity in teleost, and thus provided novel insights into the evolution of adaptive immune system.