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

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posted on 2024-05-16, 13:04 authored by Marisol Alvarez-Martinez, Luke S Cox, Claire F Pearson, William J Branchett, Probir Chakravarty, Xuemei Wu, Hubert Slawinski, Alaa Al-Dibouni, Vasileios A Samelis, Leona Gabryšová, Simon L Priestnall, Alejandro Suárez-Bonnet, Anna Mikolajczak, James Briscoe, Fiona Powrie, Anne O'Garra
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.

Funding

Crick (Grant ID: CC2084, Grant title: O'Garrra CC2084) Crick (Grant ID: CC2032, Grant title: Briscoe CC2032) Crick (Grant ID: CC1064, Grant title: STP Advanced Sequencing) Crick (Grant ID: CC1107, Grant title: STP Bioinformatics & Biostatistics) Crick (Grant ID: CC1061, Grant title: STP Experimental Histopathology)

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