These cytokine-producing CD4 + leukocytes are therefore identified as potential equivalents of Th cells in tetrapod. As with modern CD4 + Th cells, CD4 + leukocytes of many bony fish, such as zebrafish and rainbow trout, exhibit Ag-induced Th1, Th2, and Th17 cytokine responses ( 5, 10, 11). Recent advances in a variety of teleost species have revealed that their ancestral adaptive immune system is armed with the same dedicated array of fundamental weapons as that of tetrapod, including T/B lymphocytes with somatically rearranged receptors (TCRs/BCRs), CD4/MHC class II and CD8/MHC class I molecules, and reminiscent Igs IgM/D/T ( 7– 9). As fish comprise the first evolutionary group with an integral adaptive immune system, they are considered ideal models for determining fundamental immunological events, such as the origin of T/B lymphocytes as well as the evolution of regulatory mechanisms for adaptive immunity ( 3– 6). Despite remarkable progress through studies on the T cell–mediated response in mammals, our knowledge regarding T cell evolution remains limited. T cells are principal components of the adaptive immune system for vertebrates ( 1, 2). Therefore, our findings fill in an important gap regarding evolution of the adaptive immune system. From an evolutionary viewpoint, our study suggests that primordial T cells are armed with sophisticated regulatory strategies like those in modern T cells prior to the divergence of bony fish from the tetrapod lineage. To our knowledge, these results represent the first description of the regulatory mechanism for T cell–mediated adaptive immunity in a fish species. Mechanistically, teleost mTORC1 directs effector T cell function by coordinating multiple metabolic programs, including glycolysis, glutaminolysis, and lipogenesis through activating key transcription factors c-Myc, HIF-1α, and sterol regulatory element–binding proteins, and thus links immune signals to metabolic reprogramming in jawed fish. More critically, we show that signals from mTORC1 are indispensable for primordial effector T cells to eliminate infection by promoting the expression of proinflammatory cytokines, cytotoxic-related molecules, and proapoptotic genes. ![]() Blockade of mTORC1 signaling by rapamycin impairs T cell activation and Ag-induced proliferation in this early vertebrate. ![]() Nile tilapia T cells as well as a tightly regulated mammalian/mechanistic target of rapamycin complex 1 (mTORC1) pathway participate in the cellular adaptive immune response during Streptococcus agalactiae infection. To this end, using a Nile tilapia ( Oreochromis niloticus) model, we revealed the regulatory mechanism of adaptive immunity mediated by ancestral T cells in jawed fish. Biological studies of fish T cells may provide helpful evidence to understand evolution of adaptive immune systems. T cells suddenly appeared in jawed fish ∼450 million years ago.
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