PD-L1 restrains T-cell immunity in Nile tilapia by suppressing activation-induced fatty acid synthesis.

The programmed death ligand 1/programmed cell death 1 (PD-L1/PD-1) serves as a critical immune checkpoint in T cell-mediated immune responses, playing a central role in maintaining peripheral immune tolerance and homeostasis. Although early vertebrates lack a PD-1 homolog and they retain PD-L1, the functional significance and regulatory mechanisms of PD-L1 in T-cell immunity in these species remain poorly understood. In this study, using Nile tilapia (Oreochromis niloticus) as a teleost model, we systematically investigated the immunosuppressive role of PD-L1 in T-cell immunity. PD-L1 was widely expressed in various lymphoid tissues, and both its mRNA and protein levels were significantly upregulated following T-cell activation induced by mAbs against CD3/CD28 and Edwardsiella piscicida infection. Functional analyses demonstrated that exogenous PD-L1 treatment markedly suppressed T-cell activation and promoted activation-induced apoptosis. Moreover, PD-L1 treatment significantly impaired T-cell proliferation, effector cytokine production, and cytotoxic activity, ultimately compromising antibacterial immune defense. Mechanistically, activated tilapia T cells exhibited enhanced de novo fatty acid synthesis, whereas PD-L1 disrupted this metabolic reprogramming by inhibiting key enzymatic activities and reducing acetyl-CoA accumulation, ultimately leading to impaired T-cell function. Notably, restoration of fatty acid synthesis effectively reversed the PD-L1-induced immunosuppressive effects on tilapia T cells. In summary, this study reveals a previously unrecognized mechanism by which PD-L1 suppresses T-cell immunity in an early vertebrate through modulation of lipid metabolism. These findings highlight the essential role of metabolism regulation in immune checkpoint signaling and provide new evolutionary insights into the maintenance of T-cell homeostasis.