The kinases MEKK2 and MEKK3 regulate transforming growth factor-β-mediated helper T cell differentiation

Immunity. 2011 Feb 25;34(2):201-12. doi: 10.1016/j.immuni.2011.01.017. Epub 2011 Feb 17.

Abstract

Mitogen-activated protein kinases (MAPKs) are key mediators of the T cell receptor (TCR) signals but their roles in T helper (Th) cell differentiation are unclear. Here we showed that the MAPK kinase kinases MEKK2 (encoded by Map3k2) and MEKK3 (encoded by Map3k3) negatively regulated transforming growth factor-β (TGF-β)-mediated Th cell differentiation. Map3k2(-/-)Map3k3(Lck-Cre/-) mice showed an abnormal accumulation of regulatory T (Treg) and Th17 cells in the periphery, consistent with Map3k2(-/-)Map3k3(Lck-Cre/-) naive CD4(+) T cells' differentiation into Treg and Th17 cells with a higher frequency than wild-type (WT) cells after TGF-β stimulation in vitro. In addition, Map3k2(-/-)Map3k3(Lck-Cre/-) mice developed more severe experimental autoimmune encephalomyelitis. Map3k2(-/-)Map3k3(Lck-Cre/-) T cells exhibited impaired phosphorylation of SMAD2 and SMAD3 proteins at their linker regions, which negatively regulated the TGF-β responses in T cells. Thus, the crosstalk between TCR-induced MAPK and the TGF-β signaling pathways is important in regulating Th cell differentiation.

Publication types

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

MeSH terms

  • Animals
  • Bone Marrow Transplantation
  • Cell Differentiation
  • Enzyme Activation
  • Forkhead Transcription Factors / analysis
  • Lymphocyte Count
  • Lymphopenia / enzymology
  • Lymphopenia / genetics
  • Lymphopenia / pathology
  • MAP Kinase Kinase Kinase 2 / deficiency
  • MAP Kinase Kinase Kinase 2 / genetics
  • MAP Kinase Kinase Kinase 2 / physiology*
  • MAP Kinase Kinase Kinase 3 / deficiency
  • MAP Kinase Kinase Kinase 3 / genetics
  • MAP Kinase Kinase Kinase 3 / physiology*
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary
  • Receptors, Antigen, T-Cell / physiology
  • Smad2 Protein / chemistry
  • Smad2 Protein / metabolism*
  • Smad3 Protein / chemistry
  • Smad3 Protein / metabolism*
  • Specific Pathogen-Free Organisms
  • T-Lymphocytes, Helper-Inducer / cytology*
  • T-Lymphocytes, Helper-Inducer / pathology
  • T-Lymphocytes, Regulatory / chemistry
  • T-Lymphocytes, Regulatory / pathology
  • Th17 Cells / pathology
  • Transforming Growth Factor beta / physiology*

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Receptors, Antigen, T-Cell
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • MAP Kinase Kinase Kinase 2
  • MAP Kinase Kinase Kinase 3
  • Map3k2 protein, mouse
  • Map3k3 protein, mouse

Associated data

  • GEO/GSE26987