Bcl3 dependent regulation of Dendritic Cell function in Toxoplasma gondii infection

Abstract

Abstract The atypical IκB family member Bcl-3 associates with p50/NF-κB1 or p52/NF-κB2 homodimers in nuclei, thereby either positively or negatively modulating transcription in a context-dependent manner. Bcl-3 is critical for host resistance to Toxoplasma gondii and Bcl-3-deficient mice succumbed within 3–5 weeks after infection, correlating with an apparently impaired Th1-type adaptive immune response rather than a defect in the innate immune response. Surprisingly, mice lacking Bcl-3 in CD11c+ dendritic cells (DC) were as susceptible as mice globally deficient for Bcl-3, demonstrating that Bcl-3 is required in these cells to prime protective T-cell-mediated immunity to T. gondii. It remains to be determined however whether conventional or monocyte derived DCs are critical mediators of a successful T cell response against the invading pathogen. We generated mice specifically lacking Bcl-3 in conventional DCs (Zbtb46 cre knockout [KO]) or in monocyte derived DCs (LysM cre KO). Surprisingly, both conditional KO strains were as susceptible to T. gondii infection as total KO mice. Interestingly, we detected the presence of a unique subpopulation of conventional DCs that expressed the monocytic markers CD64 and Ly6C in infected spleen, which was reduced in the absence of Bcl3. Single cell RNA sequencing was done with infected splenic DCs to understand the developmental regulation of DC across genotypes. Functionally Bcl3 depleted DC are poor presenter of antigen and are defective in cross presenting toxoplasma specific antigens. Consequently, the T cells are poorly primed in these KO mouse leading to inadequate generation of inflammatory cytokines such as IFNg, which is indispensable for host protection.