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.
This paper's license is marked as closed access or non-commercial and cannot be viewed on ResearchHub. Visit the paper's external site.