Blimp-1 and c-Maf regulate common and unique gene networks to protect against distinct pathways of pathobiont-induced colitis

Abstract

ABSTRACTIntestinal immune responses to commensals and pathogens are controlled by IL-10 to avoid intestinal immune pathology. We show that the transcription factors Blimp-1(Prdm-1)and c-Maf are co-dominant regulators ofIl10in Foxp3+regulatory T cells, but also negatively regulate proinflammatory cytokines in effector T cells. Mice with T cell-specific deletion ofPrdm-1, Mafor the combination of both transcription factors did not develop inflammatory intestinal pathologies at the steady state. Double deficientPrdm1fl/flMaffl/flCd4Cremice infected withHelicobacter hepaticusdeveloped severe colitis with a major increase in TH1/NK/ILC1 effector genes in lamina propria leucocytes (LPLs), whilePrdm1fl/flCd4CreandMaffl/flCd4Cremice showed mild/moderate pathology and a less-marked Type I effector response. LPLs from infectedMaffl/flCd4Cremice showed increasedIl17aexpression and an accompanying increase in granulocytes and myeloid cells, which was less marked inPrdm1fl/flMaffl/flCd4Cremice, with increased T cell-myeloid-neutrophil interactions inferred from scRNA-seq analysis and confirmed by immunofluorescent analysis of colon sections. Genes over-expressed in human IBD showed differential expression in the LPL from infected mice in the absence ofPrdm1orMaf,revealing potential pathobiologic mechanisms of human disease.