A miR-155-Peli1-c-Rel pathway controls the generation and function of T follicular helper cells

J Exp Med. 2016 Aug 22;213(9):1901-19. doi: 10.1084/jem.20160204. Epub 2016 Aug 1.


MicroRNA (miRNA) deficiency impairs the generation of T follicular helper (Tfh) cells, but the contribution of individual miRNAs to this phenotype remains poorly understood. In this study, we performed deep sequencing analysis of miRNAs expressed in Tfh cells and identified a five-miRNA signature. Analyses of mutant mice deficient of these miRNAs revealed that miR-22 and miR-183/96/182 are dispensable, but miR-155 is essential for the generation and function of Tfh cells. miR-155 deficiency led to decreased proliferation specifically at the late stage of Tfh cell differentiation and reduced CD40 ligand (CD40L) expression on antigen-specific CD4(+) T cells. Mechanistically, miR-155 repressed the expression of Peli1, a ubiquitin ligase that promotes the degradation of the NF-κB family transcription factor c-Rel, which controls cellular proliferation and CD40L expression. Therefore, our study identifies a novel miR-155-Peli1-c-Rel pathway that specifically regulates Tfh cell generation and function.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD40 Ligand / analysis
  • Cell Differentiation
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / physiology*
  • NF-kappa B / physiology
  • Nuclear Proteins / physiology*
  • Proto-Oncogene Proteins c-rel / physiology*
  • Signal Transduction / physiology*
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Helper-Inducer / immunology*
  • Ubiquitin-Protein Ligases / physiology*


  • MicroRNAs
  • Mirn155 microRNA, mouse
  • Mirn183 microRNA, mouse
  • Mirn96 microRNA, mouse
  • NF-kappa B
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-rel
  • CD40 Ligand
  • Ubiquitin-Protein Ligases
  • Peli1 protein, mouse