{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:10:37Z","timestamp":1789017037173,"version":"build-2803163510"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Hepatic alveolar echinococcosis (HAE), a lethal chronic helminth infection caused by Echinococcus multilocularis, is characterized by pronounced local immune evasion and progressive CD8+ T cell exhaustion at the parasite?host invasive margin. However, the spatial cellular network and core regulatory subsets driving this localizedimmunosuppression remainpoorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed high-resolution spatial immune profiling of the lesion invasive margin (collagenous layer tissue, CLT) and paired distal normal liver tissues (DLT) from 12 HAE patients by integrating imaging mass cytometry, single-cell RNA sequencing, and multiplex immunofluorescence. The underlying molecular mechanism was validated via in vitro co-culture assays with or without Transwell physical separation, and the therapeutic potential was further confirmed in a delayed?treatment HAE mouse model using neutrophil depletion(anti-Ly6G) or PD-L1 blockade (anti-PD-L1).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Spatial multi-omics identified a specific subset of APC-like PD-L1 neutrophils exclusively enriched at the HAE invasive margin, which showed striking spatial co-localization and frequent membrane-to-membrane contacts with PD-1 CD8 T cells. In vitro, activated CD8 Tcells potently induced PD-L1 upregulation on neutrophils; reciprocally, PD-L1 neutrophils significantly suppressed T cell effector function (downregulating GZMB, IFN-\u03b3, and TNF-\u03b1) and upregulated exhaustion-associated transcription factors TOX and NR4A1 via a contact-dependent PD-L1\/PD-1 pathway, effects largely abolished by Transwell separation. In the HAE mouse model, both neutrophil depletion and PD-L1 blockade significantly reduced parasite burden, alleviated liver inflammation and fibrosis, and restored CD8 T cell cytotoxicity; notably, neutrophil depletion achieved superior therapeutic efficacy compared with PD-L1 monotherapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Collectively, our findings demonstrate that PD-L1-expressing neutrophils at the HAE invasivefront contribute importantly to localized CD8 T cell exhaustion via direct cell-cell contact, anddisrupting this crosstalk represents a promising targeted strategy to restore host protective immunity against parasitic infection.<\/jats:p>\n                  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