Fish NF‐κB couples TCR and IL‐17 signals to regulate ancestral T‐cell immune response against bacterial infection

Abstract

As fish constitute the first evolutionary group with primordial T cells, they are of importance for understanding the origin and evolution of adaptive immunity. Yet, the knowledge about how ancestral T cells function remains limited. Therefore, the teleost model Nile tilapia (Oreochromis niloticus) was used in this study to investigate the regulatory mechanisms of T-cell immunity in fish. We identified an evolutionarily conserved canonical NF-κB signaling pathway in Nile tilapia, which participates in primary adaptive immune response during Streptococcus agalactiae infection. Blockade of NF-κB activity severely impairs T-cell activation and expansion, rendering the animals more vulnerable to pathogen attack. Meanwhile, NF-κB signaling is indispensable for fish T cells to produce IL-17A during the antibacterial immune response. Moreover, IL-17A binds its receptor IL-17RA, initiates the ACT1-TRAF6-TAK1 axis, and triggers NF-κB-dependent T-cell activation, thus forming a positive feedback loop of T-cell immunity in Nile tilapia. Furthermore, IL-17A seems to promote innate immunity by regulating pro-inflammatory cytokines via TRAF6-NF-κB axis, indicating the presence of an NF-κB-dependent IL-17A signaling pathway for coordinating adaptive and innate immunity in fish. Our results suggest that fish NF-κB couples TCR and IL-17 signals to modulate ancestral T-cell immunity against bacterial infection, and the regulation of T-cell immunity by NF-κB and IL-17 is a strategy that existed prior to the divergence of the tetrapod lineage from teleost fish. This study, therefore, provides a new perspective on the evolution of adaptive immunity.

Evolutionarily conserved IL-27β enhances Th1 cells potential by triggering the JAK1/STAT1/T-bet axis in Nile tilapia

“…Although recent research showed that IL-27β upregulated the expression of the innate immune factors involved in T cell activation in tongue sole, there is no convincing evidence to show how this cytokine promotes adaptive immunity mediated by T cells. In our previous studies, Nile tilapia was used as a model to elucidate that several signaling pathways (namely Ca 2+ -NFAT, MAPK/Erk, NF-κB, and mTORC1) jointly support activation, proliferation, and antimicrobial immune function of teleost T cells [ 28 , [57] , [58] , [59] ]. Advances in mammal research have established that T cell activation through via Erk and JNK pathways [60] .…”

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

“…Our recent studies have demonstrated that tilapia possess well-evolved T-cell immunity and sophisticated regulatory mechanisms. For example, mTORC1 couples immune signaling with metabolic reprograming, NF-κB couples TCR and IL-17 signals, Ca 2+calcineurin axis triggers NFAT nuclear translocation, and the MAPK/ERK cascade initiates c-Myc-mediated glycolysis to ensure proper activation, proliferation, and anti-infection immune response of tilapia T cells [33][34][35][36]. On the other hand, it was reported that rainbow trout employs IgM + and IgT + B cells and corresponding antibodies to perform their respective functions in systemic and mucosal humoral immunity [74,75].…”

“…However, despite these advances, the existence of CD3 + CD4 + IFN-γ + T cells, their detailed immunological functions, and differentiation mechanisms have not been well elucidated in bony fish. Recently, using a Nile tilapia (Oreochromis niloticus) model, we demonstrated that several classical pathways, such as Ca 2+ -NFAT, MAPK/ERK, NF-κB, and mTORC1 signaling, are indispensable for the activation and proliferation of T cells and their role in fighting bacterial infection [33][34][35][36]. In the present study, we identified a population of CD3 + CD4-1 + IFN-γ + T cells (designated Th1 cells) in Nile tilapia using mAbs generated against CD3ε, CD4-1, and IFN-γ, and further investigated their immunological roles in resisting intracellular bacterial infection and the mechanism underlying their potential differentiation.…”

Glutamine Metabolism Underlies the Functional Similarity of T Cells between Nile Tilapia and Tetrapod

“…[ 33 , 34 ] In most teleost species, CD4 + T cells encode two CD4 receptors—CD4‐1 and CD4‐2, of which CD4‐1 is considered homologous to mammalian CD4. [ 35 ] The facts that Japanese flounder possesses CD4‐1 + T‐bet + lymphocytes, [ 36 ] tilapia T cells secrete IL‐17A to resist extracellular bacterial infection, [ 37 ] and CD4‐1 + T cells from HGG‐immunized zebrafish upregulate IFN‐ γ , IL‐4, and IL‐17 expression, [ 38 ] collectively indicate the potential existence and immunological function of Th‐like cells in these fishes. In addition, zebrafish CD40L promotes the thymus dependent antigen‐induced IgM + B cell proliferation and IgM production, which are inhibited by cyclosporin A (CyA)‐mediated T cell suppression, suggesting that teleost T cells also regulate humoral immunity.…”