CD4⁺ T cell-intrinsic T-bet sustains protective CNS immunity and parasite control during Toxoplasma gondii infection
Year: 2026
Type: preprint
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.
Institution: Indiana University School of Medicine
Language: English
Subfield: Parasitology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7223183953