{
  "abstract": "{beta} cell expression of the immune checkpoint ligand PD-L1 (encoded by CD274) limits autoimmune {beta} cell destruction in type 1 diabetes (T1D). {beta} cell display PD-L1 not only at the cell surface but also secreted on extracellular vesicles (EVs), which bind PD-1 and restrain CD8+ T cell activation. {beta} cell IFN signaling is an early driver of T1D pathogenesis, yet the mechanisms linking IFN signaling to the fate of PD-L1 protein remain undefined. Here, we identify an IFN- and coxsackievirus-inducible alternatively spliced isoform of PD-L1, PD-L1{Delta}3, lacking cassette exon 3 and generated in human {beta} cells and islets in response to IFN signaling or viral infection. PD-L1{Delta}3 transcripts are elevated in islets from donors with single autoantibody positivity (AAB+) and T1D. Unlike full-length PD-L1, which localizes to the plasma membrane, PD-L1{Delta}3 is retained intracellularly and loses the capacity to bind PD-1. Functionally, PD-L1{Delta}3 fails to suppress CD8+ and CD4+ T cell proliferation, activation, and cytotoxic cytokine release, and is not efficiently sorted into EVs. Convergently, a germline CD274 splice-site variant (c.682+1G>A) found in siblings with neonatal T1D yields a protein with the same intracellular retention, reduced {beta} cell PD-1 binding, and reduced {beta} cell and circulating EV PD-L1. Together these findings define PD-L1{Delta}3 as an IFN-induced splice variant that diverts PD-L1 away from its immunoregulatory, EV-competent form, revealing a post-transcriptional axis that shapes {beta} cell immune communication.",
  "abstract_shown": true,
  "affiliations": [
    "Indiana University School of Medicine"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "name": "C. Rao"
    },
    {
      "name": "F. Huang"
    },
    {
      "name": "S. Roy"
    },
    {
      "name": "M. C. Austin"
    },
    {
      "name": "M. B. Johnson"
    },
    {
      "name": "K. B. Kaylan"
    },
    {
      "name": "I. Amalraj"
    },
    {
      "name": "A. G. De Oliveira"
    },
    {
      "name": "D. L. Eizirik"
    },
    {
      "name": "C. Evans-Molina"
    },
    {
      "name": "A. K. Linnemann"
    },
    {
      "name": "J. D. Piganelli"
    },
    {
      "name": "R. Oram"
    },
    {
      "name": "R. Mirmira"
    },
    {
      "affs": [
        0
      ],
      "name": "E. K. Sims"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/93rnz2235t5v6.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.25.754099",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.25.754099v1.full",
  "id": "93rnz2235t5v6",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.25.754099v1",
  "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",
      "cell biology"
    ],
    [
      "openalex",
      "1311|Diabetes and associated disorders"
    ]
  ],
  "openalex": "W7214574802",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.25.754099v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-25",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/93rnz2235t5v6.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:24:53Z",
      "native_id": "10.64898/2026.09.25.754099",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.25.754099v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:cell biology",
      "subfield": "cell-biology"
    }
  ],
  "title": "A Novel PD-L1 Splice Isoform Modulates β Cell Communication in Response to Interferon Signaling",
  "title_text": "A Novel PD-L1 Splice Isoform Modulates β Cell Communication in Response to Interferon Signaling",
  "type": "preprint",
  "updated_at": "2026-10-30T12:24:53Z",
  "url": "https://research.draconitic.com/paper/93rnz2235t5v6",
  "venue": "bioRxiv",
  "versions": []
}