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-{gamma}-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-{gamma}-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-{gamma}-dependent antiparasitic mechanisms that restrict tachyzoite persistence during the transition to chronic infection.