miR‐132 suppresses transcription of ribosomal proteins to promote protective Th1 immunity

• Published in: EMBO reports 2019-04, Vol.20 (4), p.n/a
• Main Authors: Hewitson, James P, Shah, Kunal M, Brown, Najmeeyah, Grevitt, Paul, Hain, Sofia, Newling, Katherine, Sharp, Tyson V, Kaye, Paul M, Lagos, Dimitris
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell activation; Chronic infection; Clusters; Cytokines - biosynthesis; EMBO19; EMBO23; EMBO36; Event-related potentials; Female; Gene Expression Profiling; Gene Expression Regulation; Gene regulation; Gene Regulatory Networks; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; Immunity; Immunoregulation; Infections; Inflammation; Leishmania; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Mice; Mice, Transgenic; microRNA; MicroRNAs - genetics; miR‐132; p300-CBP Transcription Factors - metabolism; Parasites; Pathogens; Phenylephrine; Protein Binding; Proteins; Ribosomal proteins; Ribosomal Proteins - genetics; Ribosomal Proteins - metabolism; RNA Interference; Scientific Report; Scientific Reports; Spleen; Spleen - immunology; Spleen - metabolism; Spleen - microbiology; TFIID protein; Th cells; Th1 Cells - immunology; Th1 Cells - metabolism; Transcription; Transcription Factor TFIID - metabolism; γ-Interferon
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201846620

Determining the mechanisms that distinguish protective immunity from pathological chronic inflammation remains a fundamental challenge. miR‐132 has been shown to play largely immunoregulatory roles in immunity; however, its role in CD4 + T cell function is poorly understood. Here, we show that CD4 + T cells express high levels of miR‐132 and that T cell activation leads to miR‐132 up‐regulation. The transcriptomic hallmark of splenic CD4 + T cells lacking the miR‐132/212 cluster during chronic infection is an increase in mRNA levels of ribosomal protein (RP) genes. BTAF1, a co‐factor of B‐TFIID and novel miR‐132/212‐3p target, and p300 contribute towards miR‐132/212‐mediated regulation of RP transcription. Following infection with Leishmania donovani, miR‐132 −/− CD4 + T cells display enhanced expression of IL‐10 and decreased IFNγ. This is associated with reduced hepatosplenomegaly and enhanced pathogen load. The enhanced IL‐10 expression in miR‐132 −/− Th1 cells is recapitulated in vitro following treatment with phenylephrine, a drug reported to promote ribosome synthesis. Our results uncover that miR‐132/212‐mediated regulation of RP expression is critical for optimal CD4 + T cell activation and protective immunity against pathogens. Synopsis The miR‐132/212 cluster plays important roles in acute inflammation and infection. This study shows that during pathogen‐induced chronic inflammation miR‐132‐mediated regulation of ribosomal protein expression is critical for CD4 + T cell activation and protective immunity. Up‐regulation of the miR‐132/212 cluster suppresses ribosomal protein (RP) expression in Th1 cells. The miR‐132/212 cluster targets BTAF1 and p300, which control RP gene transcription. RP levels in Leishmania ‐infected miR‐132/212 −/− mice correlate with increased IL‐10 expression in Th1 cells. Infected miR‐132/212 −/− mice show reduced hepatosplenomegaly and increased parasite burdens. Graphical Abstract The miR‐132/212 cluster plays important roles in acute inflammation and infection. This study shows that during pathogen‐induced chronic inflammation miR‐132‐mediated regulation of ribosomal protein expression is critical for CD4 + T cell activation and protective immunity.