{
  "abstract": "Chronic or persistent T cell activation is widely thought to culminate in T cell exhaustion, yet how autoreactive CD8+ 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+ PD-1+ 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 (Dnase2a-/- Ifnar1-/-) 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+ 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+ TOX+ T cells, defining a locally operating progenitor-to-effector pipeline. Spatial transcriptomics positioned these intrahepatic T cell clusters adjacent to IL-27-expressing inflammatory macrophages, and disruption of IL-27 or its receptor in bone marrow-derived cells reduced PD-1+ CD8+ 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 PD-1+ CD8+ T cell program in situ.",
  "abstract_shown": true,
  "affiliations": [
    "Umass Chan Medical School"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "name": "K. Hao"
    },
    {
      "name": "S. G. Baptista"
    },
    {
      "name": "A. S. V. Beaumond"
    },
    {
      "name": "D. M. Schafer"
    },
    {
      "name": "P. L. Kaja"
    },
    {
      "name": "K. Chiang"
    },
    {
      "name": "K. M. Gao"
    },
    {
      "name": "K. Nundel"
    },
    {
      "name": "S. V. Kumar"
    },
    {
      "name": "M. S. Sherman"
    },
    {
      "name": "A. Marshak-Rothstein"
    },
    {
      "affs": [
        0
      ],
      "name": "S. K. Varanasi"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4tepnnefp9619.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.25.754422",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.25.754422v1.full",
  "id": "4tepnnefp9619",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.25.754422v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "immunology"
    ],
    [
      "openalex",
      "2403|T-cell and B-cell Immunology"
    ]
  ],
  "openalex": "W7214734722",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.25.754422v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-25",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/4tepnnefp9619.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:25:02Z",
      "native_id": "10.64898/2026.09.25.754422",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.25.754422v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:immunology",
      "subfield": "immunology"
    }
  ],
  "title": "Macrophage-derived IL-27 sustains autoreactive CD8+ cytotoxic T cells in autoimmune hepatitis",
  "title_text": "Macrophage-derived IL-27 sustains autoreactive CD8+ cytotoxic T cells in autoimmune hepatitis",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:02Z",
  "url": "https://research.draconitic.com/paper/4tepnnefp9619",
  "venue": "bioRxiv",
  "versions": []
}