Iron Drives T Helper Cell Pathogenicity by Promoting RNA-Binding Protein PCBP1-Mediated Proinflammatory Cytokine Production

Immunity. 2018 Jul 17;49(1):80-92.e7. doi: 10.1016/j.immuni.2018.05.008. Epub 2018 Jun 26.


Iron deposition is frequently observed in human autoinflammatory diseases, but its functional significance is largely unknown. Here we showed that iron promoted proinflammatory cytokine expression in T cells, including GM-CSF and IL-2, via regulating the stability of an RNA-binding protein PCBP1. Iron depletion or Pcbp1 deficiency in T cells inhibited GM-CSF production by attenuating Csf2 3' untranslated region (UTR) activity and messenger RNA stability. Pcbp1 deficiency or iron uptake blockade in autoreactive T cells abolished their capacity to induce experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. Mechanistically, intracellular iron protected PCBP1 protein from caspase-mediated proteolysis, and PCBP1 promoted messenger RNA stability of Csf2 and Il2 by recognizing UC-rich elements in the 3' UTRs. Our study suggests that iron accumulation can precipitate autoimmune diseases by promoting proinflammatory cytokine production. RNA-binding protein-mediated iron sensing may represent a simple yet effective means to adjust the inflammatory response to tissue homeostatic alterations.

Keywords: 3′ UTR; CLIP; EAE; GM-CSF; PCBP1; RNA; RNA-binding protein; T cells; iron; post-transcription regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Binding Sites
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cytokines / biosynthesis*
  • Cytokines / genetics
  • DNA-Binding Proteins
  • Encephalomyelitis, Autoimmune, Experimental / metabolism*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Female
  • Humans
  • Iron / agonists
  • Iron / deficiency
  • Iron / metabolism*
  • Mice
  • Multiple Sclerosis / metabolism
  • Multiple Sclerosis / pathology
  • RNA Processing, Post-Transcriptional
  • RNA Stability / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Receptors, Transferrin / deficiency
  • T-Lymphocytes, Helper-Inducer / metabolism*
  • T-Lymphocytes, Helper-Inducer / pathology*
  • T-Lymphocytes, Helper-Inducer / transplantation


  • 3' Untranslated Regions
  • Carrier Proteins
  • Csf2ra protein, mouse
  • Cytokines
  • DNA-Binding Proteins
  • Pcbp1 protein, mouse
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Receptors, Transferrin
  • Tfrc protein, mouse
  • Iron