The Francis Crick Institute
s41590-024-01814-z (2).pdf (33.63 MB)

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

Download (33.63 MB)
journal contribution
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.


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)