Tbet-expressing Tregs protect against lethal immunopathology during T. gondii infection

Abstract

Abstract Toxoplasma gondii infection has proven to be an ideal model to understand the delicate balance between protective immunity and immune mediated pathology. Tregs are necessary for maintaining immune homeostasis, particularly in the gut where immune tolerance to food and the microbiota is tightly regulated. Oral infection with T. gondii leads to a robust Th1 immune response initiating in the GI tract and has also been implicated in dysbiosis associated with inflammatory bowel disease. During T. gondii infection, Tregs highly express the Th1 lineage specifying transcription factor, Tbet, throughout infection. To determine the role of Tbet in Tregs, we infected Tbetf/f-Foxp3YFPCre and control Foxp3YFPCre mice with the type II strain ME49 T. gondii, Surprisingly, greater than 75% Tbetf/f-Foxp3YFPCre mice succumb to infection at peak acute infection while nearly 100% of the control Foxp3YFPCre mice survive. Analysis of parasite burden showed Tbetf/f-Foxp3YFPCre mice controlled the infection. Tbetf/f-Foxp3YFPCre mice did not control the Th1 mediated inflammation, which lead to immune mediated pathology. Depletion of CD4+ T cells and antibiotic treatment ameliorates morbidity in Tbetf/f-Foxp3YFPCre mice. While loss of Tbet in Tregs lead to higher frequencies and numbers of Tregs, these cells were still unable to prevent lethal immunopathology. RNA-seq analysis reveals that Tbet regulates several key cellular pathways and developmental processes that enhance the Treg’s ability to suppress immune response in a Th1 environment. Taken together, our data highlights an essential role for Tbet in Tregs to prevent lethal immunopathology during acute Toxoplasma gondii infection.