{
  "abstract": "The transcription factor T-bet is widely regarded as the master regulator of type 1 immunity and is considered essential for host resistance to intracellular pathogens. Previous studies have demonstrated that global T-bet deficiency causes profound susceptibility to intracellular pathogens, including T . gondii . However, the specific cell-intrinsic requirement for T-bet within CD4⁺ T cells has remained unclear because T-bet regulates multiple innate and adaptive immune populations that contribute to protective immunity. Therefore, to define the cell-intrinsic role of T-bet in CD4⁺ T cells during infection, we utilized mice with conditional T-bet deletion in CD4⁺ T cells (CD4- Tbx21 −/− ) and found that CD4⁺ T cell-intrinsic T-bet was largely dispensable for acute parasite control and the generation of antigen-experienced IFN-γ-producing CD4⁺ T cells. However, although CD4- Tbx21 −/− mice controlled acute infection, our data reveal that as infection transitions to the chronic stage, CD4⁺ T cell-intrinsic T-bet becomes critical for sustaining cerebral immunity, promoting IFN-γ-dependent antimicrobial responses, and maintaining parasite control within the brain. Collectively, our findings establish that CD4⁺ T cell-intrinsic T-bet is required for sustaining protective CD4⁺ T cell responses within the infected CNS and promotes IFN-γ-dependent antiparasitic mechanisms that restrict tachyzoite persistence during the transition to chronic infection.\n\nAuthor Summary: Toxoplasma gondii is an intracellular parasite that can establish lifelong infection in the brain, where continuous immune responses are required to prevent parasite reactivation and disease. CD4⁺ T cells are central to this protection, and their effector functions are commonly associated with the transcription factor T-bet, a key regulator of type 1 immunity. Our previous work demonstrated that T-bet-dependent IFN-γ from innate lymphoid cells is essential for maintaining inflammatory dendritic cells during infection, yet CD4⁺ T cells can still produce IFN-γ even without T-bet. This raised the question of whether T-bet is truly required within CD4⁺ T cells to control T. gondii . To address this, we used mice lacking T-bet specifically in CD4⁺ T cells. Notably, these mice controlled early infection and generated IFN-γ-producing CD4⁺ T cells, demonstrating that T-bet is not strictly required to initiate these protective responses. However, as infection progressed, the absence of T-bet compromised the long-term maintenance of protective CD4⁺ T cell responses in the brain, resulting in impaired antimicrobial defenses and increased parasite persistence. Our findings reveal that the importance of T-bet in CD4⁺ T cells changes over the course of infection, becoming particularly critical for sustaining protective immunity in the central nervous system. These results provide new insight into how CD4⁺ T cells maintain control of persistent intracellular pathogens.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "name": "Daisy Woellner-Santos",
      "orcid": "0009-0001-9758-1504"
    },
    {
      "name": "Kamryn Zadeii"
    },
    {
      "name": "Rian DelVecchio"
    },
    {
      "name": "Mia Somenzi",
      "orcid": "0009-0002-5029-6623"
    },
    {
      "name": "Américo López-Yglesias",
      "orcid": "0000-0001-6797-2179"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fbgsswhjv9wkf.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.15.759516",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.15.759516v1.full",
  "id": "fbgsswhjv9wkf",
  "issns": [
    "2692-8205"
  ],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.15.759516v1",
  "language": "en",
  "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"
    ],
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2405|Toxoplasma gondii Research Studies"
    ]
  ],
  "openalex": "W7223183953",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.15.759516v1.full.pdf",
  "pmcid": "PMC13738467",
  "pmid": "42995844",
  "published": "2026-10-15",
  "publisher": "Cold Spring Harbor Laboratory Preprints",
  "ris": "https://research.draconitic.com/paper/fbgsswhjv9wkf.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:29:00Z",
      "native_id": "10.64898/2026.10.15.759516",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.15.759516v1"
    },
    {
      "first_seen": "2026-11-09T12:23:26Z",
      "native_id": "PMC13738467",
      "source": "pmc",
      "url": "https://doi.org/10.64898/2026.10.15.759516"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:immunology",
      "subfield": "immunology"
    }
  ],
  "title": "CD4+ T cell-intrinsic T-bet sustains protective CNS immunity and parasite control during Toxoplasma gondii infection",
  "title_text": "CD4+ T cell-intrinsic T-bet sustains protective CNS immunity and parasite control during Toxoplasma gondii infection",
  "type": "preprint",
  "updated_at": "2026-11-09T12:23:26Z",
  "url": "https://research.draconitic.com/paper/fbgsswhjv9wkf",
  "venue": "bioRxiv",
  "versions": []
}