PD-1 Deficiency Impairs Treg Differentiation in Trichinella-Infected Mice Via Inhibition of Fatty Acid Oxidation

Helminth infections establish long-term host persistence by inducing regulatory immune responses that limit pathology while promoting parasite survival. Programmed death 1 (PD-1), an inhibitory receptor expressed on activated T cells, plays an essential role in maintaining immune homeostasis during chronic infections. Regulatory T cells (Tregs) expand during helminth infection and are critical for controlling excessive inflammation; however, the metabolic mechanisms linking PD-1 signaling to Treg differentiation during helminth infection remain poorly defined. Here, we investigated the role of PD-1 in regulating Treg differentiation during Trichinella spiralis infection, focusing on metabolic reprogramming in CD4⁺ T cells. Using a murine infection model, we compared wild-type and PD-1–deficient (PD-1⁻/⁻) mice and evaluated Treg differentiation in vivo and in a bone marrow-derived dendritic cell (BMDC)–CD4⁺ T-cell co-culture system stimulated with muscle larval excretory–secretory products (MES). PD-1 deficiency significantly reduced splenic FoxP3⁺ Treg frequencies following infection and impaired MES-induced Treg differentiation and Treg-associated cytokine production in vitro. Metabolic profiling revealed that CD4⁺ T cells from infected PD-1⁻/⁻ mice exhibited markedly reduced fatty acid oxidation (FAO), accompanied by decreased expression of Carnitine Palmitoyltransferase 1A (CPT1A), a key rate-limiting enzyme in FAO. Mechanistic analyses demonstrated that PD-1 deficiency suppressed AMPK activation while enhancing PI3K–Akt–mTOR signaling. Importantly, pharmacological inhibition of PI3K partially restored FAO activity and rescued Treg differentiation in PD-1⁻/⁻ CD4⁺ T cells. Collectively, our findings identify PD-1 as a critical metabolic regulator of Treg development during T. spiralis infection by promoting CPT1A-dependent FAO. This study reveals a previously unrecognized PD-1–mediated metabolic–immune axis that contributes to helminth-induced immune regulation and highlights potential metabolic targets for modulating host responses in chronic helminth infections.