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

Abstract

ABSTRACT Intestinal 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 of Il10 in Foxp3 + regulatory T cells, but also negatively regulate proinflammatory cytokines in effector T cells. Mice with T cell-specific deletion of Prdm-1, Maf or the combination of both transcription factors did not develop inflammatory intestinal pathologies at the steady state. Double deficient Prdm1 fl/fl Maf fl/fl Cd4 Cre mice infected with Helicobacter hepaticus developed severe colitis with a major increase in TH1/NK/ILC1 effector genes in lamina propria leucocytes (LPLs), while Prdm1 fl/fl Cd4 Cre and Maf fl/fl Cd4 Cre mice showed mild/moderate pathology and a less-marked Type I effector response. LPLs from infected Maf fl/fl Cd4 Cre mice showed increased Il17a expression and an accompanying increase in granulocytes and myeloid cells, which was less marked in Prdm1 fl/fl Maf fl/fl Cd4 Cre mice, 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 of Prdm1 or Maf, revealing potential pathobiologic mechanisms of human disease.