NF kappa B regulator Bcl3 controls development and function of classical dendritic cells required for resistance to Toxoplasma gondii

Abstract

The atypical IκB family member Bcl3 associates with p50/NF-κB1 or p52/NF-κB2 homodimers in the nucleus, and positively or negatively modulates transcription in a context-dependent manner. In mice lacking Bcl3 globally or specifically in CD11c+cells, we previously reported thatToxoplasma gondiiinfection is uniformly fatal and is associated with an impaired Th1 immune response. Since Bcl3 expression in dendritic cells (DC) is pivotal for antigen presentation and since classical DCs (cDC) are major antigen presenting cells, we investigated the role of Bcl3 specifically in cDCsin vivoby crossing Zbtb46 cre mice withBcl3flx/flxmice.Bcl3flx/flxZbtb46 cremice were as susceptible to lethalT.gondiiinfection as totalBcl3-/-mice and generated poor Th1 immune responses. Consistent with this, compared to wildtype controls, splenic Xcr1+Bcl3-deficient cDC1 cells were defective in presenting Ova antigen to OT-I cells both for Ova257-264peptide and after infection with Ovalbumin-expressingT.gondii. Moreover, splenic CD4+and CD8+T cells from infectedBcl3flx/flxZbtb46 cremice exhibited decreasedT.gondii-specific priming as revealed by both reduced cytokine production and reducedT.gondii-specific tetramer staining.In vitrodifferentiation of cDCs from bone marrow progenitors also revealed Bcl3-dependent cDC-specific antigen-presentation activity. Consistent with this, splenocyte single cell RNA seq (scRNAseq) in infected mice revealed Bcl3-dependent expression of genes involved in antigen processing in cDCs. We also identified by scRNAseq, a unique Bcl3-dependent hybrid subpopulation of Zbtb46+DCs co-expressing the monocyte/macrophage transcription factor Lysozyme M. This subpopulation exhibited Bcl3-dependent expansion after infection. Likewise, by flow cytometry we identified twoT.gondii-induced hybrid subpopulations of Bcl3-dependent cDC1 and cDC2 cells both expressing monocyte/macrophage markers, designated as icDC1 and icDC2. Together, our results indicate that Bcl3 in classical DCs is a major determinant of protective T cell responses and survival inT.gondii-infection.