{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:56:04Z","timestamp":1790794564117,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,28]]},"group-title":"Immunology","reference-count":90,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,28]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  Chronic or persistent T cell activation is widely thought to culminate in T cell exhaustion, yet how autoreactive CD8\u207a T cells remain functionally intact despite sustained self-antigen exposure is poorly understood. In chronic infection and cancer this durability is attributed to stem-like, TCF1\u207a PD-1\u207a progenitor-exhausted (Tpex) cells that reside in lymphoid tissue and continuously replenish functional effectors; whether such a reservoir operates within a chronically inflamed peripheral organ during sterile autoimmunity is unknown. Here we show that mice lacking the lysosomal nuclease DNase2a together with the type I interferon receptor Ifnar1 (\n                  <jats:italic>Dnase2a\u207b\/\u207bIfnar1\u207b\/\u207b<\/jats:italic>\n                  ) develop spontaneous, progressive hepatic inflammation. This hepatitis was dependent on the endosomal DNA sensor TLR9, identifying self-DNA as the initiating ligand. Inflammation was marked by expansion of inflammatory macrophages and accumulation of CD8\u207a T cells co-expressing PD-1 and TOX that retained, rather than lost, effector function. Paired single-cell TCR and transcriptomic analysis revealed progenitor-exhausted T cells within the liver itself that shared clonotypes with clonally expanded PD-1\n                  <jats:sup>+<\/jats:sup>\n                  TOX\n                  <jats:sup>+<\/jats:sup>\n                  T cells, defining a locally operating progenitor-to-effector pipeline. Spatial transcriptomics positioned these intrahepatic T cell clusters adjacent to IL-27\u2013expressing inflammatory macrophages, and disruption of IL-27 or its receptor in bone marrow\u2013derived cells reduced PD-1\u207a CD8\u207a T cells and their effector functions. These findings define a novel mechanism for sustaining autoreactive T cells in the liver via TLR9-driven macrophage-induced IL-27 circuit that sustains a functional, self-renewing autoreactive PD1\n                  <jats:sup>+<\/jats:sup>\n                  CD8\u207a T cell program in situ.\n                <\/jats:p>","DOI":"10.64898\/2026.09.25.754422","type":"posted-content","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:35:13Z","timestamp":1790663713000},"source":"Crossref","is-referenced-by-count":0,"title":["Macrophage-derived IL-27 sustains autoreactive CD8\n                  <sup>+<\/sup>\n                  cytotoxic T cells in autoimmune hepatitis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1250-3935","authenticated-orcid":false,"given":"Kaiyuan","family":"Hao","sequence":"first","affiliation":[{"name":"Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA"},{"name":"Division of Rheumatology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia Grace","family":"Baptista","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA"},{"name":"Division of Rheumatology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurora Stephania Virginia","family":"Beaumond","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Milo","family":"Schafer","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5855-1006","authenticated-orcid":false,"given":"Kevin MingJie","family":"Gao","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA"},{"name":"Division of Rheumatology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasanthi Lalitha","family":"Kaja","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy","family":"Chiang","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"N\u00fcndel","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sushmitha Vijaya","family":"Kumar","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc Samuel","family":"Sherman","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department 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