Blimp-1 and c-Maf regulate immune gene networks to protect against distinct pathways of pathobiont-induced colitis
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Marisol Alvarez Martinez Luke Samuel Cox Claire F Pearson William Branchett Probir Chakravarty Xuemei Wu Hubert Slawinski Alaa Al-Dibouni Vasileios Samelis Leona Gabrysova Simon Priestnall Alejandro Suárez-Bonnet Anna Mikolajczak James Briscoe Fiona Powrie Anne O'GarraAbstract
Intestinal 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 Prdm1fl/flMaffl/flCd4Cre mice infected with Helicobacter hepaticus developed severe colitis with an increase in TH1/NK/ILC1 effector genes in LPLs, while Prdm1fl/flCd4Cre and Maffl/flCd4Cre mice exhibited moderate pathology and a less-marked type 1 effector response. LPLs from infected Maffl/flCd4Cre 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.
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Journal
Nature Immunology
Volume
25
Issue number
5
Pages
886-901
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10.1038/s41590-024-01814-z
Europe PubMed Central
38609547
Pubmed
38609547
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