CD4+ T cell-intrinsic T-bet sustains protective CNS immunity and parasite control during Toxoplasma gondii infection
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.
Author 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.
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BibTeX
@misc{woellnersantos2026cellintrinsic,
title = {{CD4+ T cell-intrinsic T-bet sustains protective CNS immunity and parasite control during Toxoplasma gondii infection}},
author = {Daisy Woellner-Santos and Kamryn Zadeii and Rian DelVecchio and Mia Somenzi and Américo López-Yglesias},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.15.759516},
url = {https://www.biorxiv.org/content/10.64898/2026.10.15.759516v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - CD4+ T cell-intrinsic T-bet sustains protective CNS immunity and parasite control during Toxoplasma gondii infection
AU - Daisy Woellner-Santos
AU - Kamryn Zadeii
AU - Rian DelVecchio
AU - Mia Somenzi
AU - Américo López-Yglesias
PY - 2026
DA - 2026/10/15
PB - bioRxiv
DO - 10.64898/2026.10.15.759516
UR - https://www.biorxiv.org/content/10.64898/2026.10.15.759516v1
AB - 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. Author 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.
SN - 2692-8205
ER -