AbstractIntestinal immune responses to microbes are controlled by the cytokine IL-10 to avoid immune pathology. Here, we use single-cell RNA sequencing of colon lamina propria leukocytes (LPLs) along with RNA-seq and ATAC-seq of purified CD4⁺ T cells to show that the transcription factors Blimp-1 (encoded by Prdm1) and c-Maf co-dominantly regulate Il10 while negatively regulating proinflammatory cytokines in effector T cells. Double-deficient Prdm1^fl/flMaf^fl/flCd4^Cre mice infected with Helicobacter hepaticus developed severe colitis with an increase in T_H1/NK/ILC1 effector genes in LPLs, while Prdm1^fl/flCd4^Cre and Maf^fl/flCd4^Cre mice exhibited moderate pathology and a less-marked type 1 effector response. LPLs from infected Maf^fl/flCd4^Cre mice had increased type 17 responses with increased Il17a and Il22 expression and an increase in granulocytes and myeloid cell numbers, resulting in increased T cell–myeloid–neutrophil interactions. Genes over-expressed in human inflammatory bowel disease showed differential expression in LPLs from infected mice in the absence of Prdm1 or Maf, revealing potential mechanisms of human disease.