{
  "abstract": "During chronic infection, the persistence of antigen and inflammation leads to the differentiation of CD8+ T cells into an exhausted state characterised by expression of inhibitory receptors (IRs) and the progressive loss of T cell functions. Among the different subsets of exhausted CD8+ T (Tex) cells, Tex progenitors expressing SLAMF6 and the transcription factor TCF-1 (TCF-1+) give rise to Tex effector-like cells expressing CX3CR1 and Tex terminal cells expressing CD101. PD-1/PD-L1 blockade acts on TCF-1+ Tex progenitor cells and promotes their differentiation into Tex effector-like cells. The molecular events controlling CD8+ Tex cell differentiation are still poorly defined. As Notch signaling may be sustained during chronic infection by persistent TCR stimulation and inflammation, we tested whether Notch signaling influences CD8+ T cell exhaustion. Using mice lacking (N1N2{triangleup}/{triangleup}) or not (N1N2fl/fl) Notch1/2 expression only in mature CD8+ T cells, we showed that the absence of Notch signal causes severe CD8+ T cell exhaustion during chronic LCMV infection. N1N2{triangleup}/{triangleup} Tex cells express higher levels of IRs and are less functional when compared to their wild-typee counterpart. In the absence of N1N2 receptors, Tex progenitor and Tex terminal cells accumulate and Tex cells cannot be reinvigorated by PD-1/PD-L1 blockade. We further demonstrated that Notch signaling is essential to promote the differentiation of Tex progenitors into Tex effector-like cells. Moreover, Notch signals, provided by stromal cells expressing the ligands Delta-like 1 and 4, are necessary during all stages of the infection to prevent severe exhaustion. Single-nucleus RNA and ATAC multiome profiling identifies Notch signaling as a critical role on effector transcriptional programming in exhausted CD8 T cells. Loss of Notch signaling impairs transcriptional program associated with migration and perception of CD4+ T cell help. Together, these alterations drive the differentiation of Tex progenitor cells toward a terminally exhausted Tex fate.",
  "abstract_shown": true,
  "affiliations": [
    "IRCM"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "name": "D. Maurice De Sousa"
    },
    {
      "name": "S. Boulet"
    },
    {
      "name": "F. Duval"
    },
    {
      "name": "E. Perkey"
    },
    {
      "name": "J.-F. Daudelin"
    },
    {
      "name": "L. Le Corre"
    },
    {
      "name": "M.-E. Lebel"
    },
    {
      "name": "A. Lamarre"
    },
    {
      "name": "F. Radtke"
    },
    {
      "name": "B. Ludewig"
    },
    {
      "name": "C. W. Siebel"
    },
    {
      "name": "I. Maillard"
    },
    {
      "affs": [
        0
      ],
      "name": "N. Labrecque"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/25661fn3vhd88.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.01.748651",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.01.748651v1.full",
  "id": "25661fn3vhd88",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.01.748651v1",
  "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": "W7210293744",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.01.748651v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/25661fn3vhd88.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:40Z",
      "native_id": "10.64898/2026.09.01.748651",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.01.748651v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:immunology",
      "subfield": "immunology"
    }
  ],
  "title": "The Notch signaling pathway is a master regulator of CD8+ T cell exhaustion and differentiation during chronic infection",
  "title_text": "The Notch signaling pathway is a master regulator of CD8+ T cell exhaustion and differentiation during chronic infection",
  "type": "preprint",
  "updated_at": "2026-10-30T12:19:40Z",
  "url": "https://research.draconitic.com/paper/25661fn3vhd88",
  "venue": "bioRxiv",
  "versions": []
}