NF-κB/mTOR/MYC Axis Drives PRMT5 Protein Induction After T Cell Activation via Transcriptional and Non-transcriptional Mechanisms

Front Immunol. 2019 Mar 19:10:524. doi: 10.3389/fimmu.2019.00524. eCollection 2019.

Abstract

Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) mediated by CD4+ T cells and modeled via experimental autoimmune encephalomyelitis (EAE). Inhibition of PRMT5, the major Type II arginine methyltransferase, suppresses pathogenic T cell responses and EAE. PRMT5 is transiently induced in proliferating memory inflammatory Th1 cells and during EAE. However, the mechanisms driving PRMT5 protein induction and repression as T cells expand and return to resting is currently unknown. Here, we used naive mouse and memory mouse and human Th1/Th2 cells as models to identify mechanisms controlling PRMT5 protein expression in initial and recall T cell activation. Initial activation of naive mouse T cells resulted in NF-κB-dependent transient Prmt5 transcription and NF-κB, mTOR and MYC-dependent PRMT5 protein induction. In murine memory Th cells, transcription and miRNA loss supported PRMT5 induction to a lesser extent than in naive T cells. In contrast, NF-κB/MYC/mTOR-dependent non-transcriptional PRMT5 induction played a major role. These results highlight the importance of the NF-κB/mTOR/MYC axis in PRMT5-driven pathogenic T cell expansion and may guide targeted therapeutic strategies for MS.

Keywords: PRMT5; T cell; memory; multiple sclerosis; naive; signaling.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Lymphocyte Activation / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Multiple Sclerosis / genetics
  • NF-kappa B / genetics*
  • Protein-Arginine N-Methyltransferases / genetics*
  • Proto-Oncogene Proteins c-myc / genetics*
  • TOR Serine-Threonine Kinases / genetics*
  • Th1 Cells / physiology
  • Th2 Cells / physiology
  • Transcription, Genetic / genetics*

Substances

  • NF-kappa B
  • Proto-Oncogene Proteins c-myc
  • Prmt5 protein, mouse
  • Protein-Arginine N-Methyltransferases
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases