{ "abstract": "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. PD-1 deficiency was associated with enhanced PI3K–Akt–mTOR signaling and suppressed AMPK activation. Importantly, pharmacological inhibition of PI3K partially restored FAO activity and rescued Treg differentiation in PD-1⁻/⁻ CD4⁺ T cells. These findings suggest that PD-1 supports Treg development during T. spiralis infection, at least in part, through a CPT1A-associated FAO pathway, highlighting a PD-1–associated metabolic pathway that may contribute to helminth-induced immune regulation. Author summary: Parasitic worms can survive in the host for long periods by shaping the immune system to reduce excessive inflammation. Regulatory T cells (Tregs) are important immune cells that help limit inflammation during worm infections, but the mechanisms controlling their development are not fully understood. Programmed death 1 (PD-1) is an immune checkpoint molecule known to regulate immune responses, yet its role in shaping Treg development during parasitic infections remains unclear. In this study, we used a mouse model of Trichinella spiralis infection to investigate how PD-1 influences Treg formation. We found that mice lacking PD-1 developed fewer Tregs during infection. Further experiments showed that PD-1 helps Treg development by regulating how immune cells use energy. Specifically, PD-1 promoted the use of fatty acids as an energy source by increasing the expression of a key metabolic enzyme. When this metabolic pathway was impaired, Treg development was reduced, but it could be partially restored using targeted metabolic inhibitors. Our findings reveal a link between immune checkpoint signaling and cellular metabolism during parasitic infection. Understanding this regulatory pathway may help identify new strategies for controlling inflammation and improving treatments for parasitic diseases and immune-related disorders.", "abstract_shown": true, "affiliations": [ "Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Capital Medical University, Beijing, China" ], "article_type": "Research Article", "arxiv": null, "author_total": 7, "authors": [ { "affs": [ 0 ], "name": "Yao Zhang" }, { "name": "Yuwan Hao" }, { "name": "Chen Wu" }, { "name": "Caiyuan Li" }, { "name": "Jingjing Huang" }, { "name": "Xinping Zhu" }, { "name": "Yuli Cheng" } ], "bibtex": "https://research.draconitic.com/paper/2c5d3tknke8hc.bib", "cited_by": 0, "doi": "10.1371/journal.pntd.0014856", "fulltext_url": "https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014856", "id": "2c5d3tknke8hc", "issns": [ "1935-2735" ], "landing_url": "https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014856", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "plos", "/Biology and life sciences/Cell biology/Cell physiology/Cell metabolism" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/T cells/Regulatory T cells" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/T helper cells" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/T cells/Regulatory T cells" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/T helper cells" ], [ "plos", "/Biology and life sciences/Developmental biology/Cell differentiation" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/T cells/Regulatory T cells" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/T helper cells" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/T cells/Regulatory T cells" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/T helper cells" ], [ "plos", "/Medicine and health sciences/Medical conditions/Parasitic diseases" ], [ "plos", "/Medicine and health sciences/Medical conditions/Parasitic diseases/Helminth infections" ], [ "plos", "/Research and analysis methods/Animal studies/Experimental organism systems/Animal models/Mouse models" ], [ "plos", "/Research and analysis methods/Animal studies/Experimental organism systems/Model organisms/Mouse models" ], [ "plos", "/Research and analysis methods/Model organisms/Mouse models" ], [ "plos", "/Research and analysis methods/Spectrum analysis techniques/Spectrophotometry/Cytophotometry/Flow cytometry" ] ], "openalex": null, "pdf_url": "https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0014856&type=printable", "pmcid": null, "pmid": null, "published": "2026-11-05", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/2c5d3tknke8hc.ris", "sources": [ { "first_seen": "2026-11-06T12:20:42Z", "native_id": "10.1371/journal.pntd.0014856", "source": "plos", "url": "https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014856" } ], "subjects": [ { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" }, { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" } ], "title": "PD-1 deficiency impairs Treg differentiation in Trichinella-infected mice via inhibition of fatty acid oxidation", "title_text": "PD-1 deficiency impairs Treg differentiation in Trichinella-infected mice via inhibition of fatty acid oxidation", "type": "peer-reviewed", "updated_at": "2026-11-07T12:20:24Z", "url": "https://research.draconitic.com/paper/2c5d3tknke8hc", "venue": "PLOS Neglected Tropical Diseases", "versions": [] }