TRIF-GEFH1-RhoB pathway is involved in MHCII expression on dendritic cells that is critical for CD4 T-cell activation

Hokuto Kamon; Takaya Kawabe; Hidemitsu Kitamura; Jihye Lee; Daisuke Kamimura; Tsuneyasu Kaisho; Shizuo Akira; Akihiro Iwamatsu; Hisashi Koga; Masaaki Murakami; Toshio Hirano

doi:10.1038/sj.emboj.7601286

TRIF-GEFH1-RhoB pathway is involved in MHCII expression on dendritic cells that is critical for CD4 T-cell activation

EMBO J. 2006 Sep 6;25(17):4108-19. doi: 10.1038/sj.emboj.7601286. Epub 2006 Aug 17.

Authors

Hokuto Kamon¹, Takaya Kawabe, Hidemitsu Kitamura, Jihye Lee, Daisuke Kamimura, Tsuneyasu Kaisho, Shizuo Akira, Akihiro Iwamatsu, Hisashi Koga, Masaaki Murakami, Toshio Hirano

Affiliation

¹ Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan.

Abstract

Dendritic cells (DC) play a central role in immune responses by presenting antigenic peptides to CD4+ T cells through MHCII molecules. Here, we demonstrate a TRIF-GEFH1-RhoB pathway is involved in MHCII surface expression on DC. We show the TRIF (TIR domain-containing adapter inducing IFNbeta)- but not the myeloid differentiation factor 88 (MyD88)-dependent pathway of lipopolysaccharide (LPS)-signaling in DC is crucial for the MHCII surface expression, followed by CD4+ T-cell activation. LPS increased the activity of RhoB, but not of RhoA, Cdc42, or Rac1/2 in a manor dependent on LPS-TRIF- but not LPS-Myd88-signaling. RhoB colocalized with MHCII+ lysosomes in DC. A dominant-negative (DN) form of RhoB (DN-RhoB) or RhoB's RNAi in DC inhibited the LPS-induced MHCII surface expression. Moreover, we found GEFH1 associated with RhoB, and DN-GEFH1 or GEFH1's RNAi suppressed the LPS-mediated RhoB activation and MHCII surface expression. DN-RhoB attenuated the DC's CD4+ T-cell stimulatory activity. Thus, our results provide a molecular mechanism relating how the MHCII surface expression is regulated during the maturation stage of DC. The activation of GEFH1-RhoB through the TRIF-dependent pathway of LPS in DC might be a critical target for controlling the activation of CD4+ T cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Adaptor Proteins, Vesicular Transport / genetics
Adaptor Proteins, Vesicular Transport / physiology*
Animals
CD4-Positive T-Lymphocytes / immunology*
CD4-Positive T-Lymphocytes / metabolism
Cells, Cultured
Dendritic Cells / drug effects
Dendritic Cells / immunology*
Dendritic Cells / metabolism
Guanine Nucleotide Exchange Factors / physiology*
Histocompatibility Antigens Class II / biosynthesis*
Lipopolysaccharides / pharmacology
Lymphocyte Activation
Mice
Mice, Inbred C57BL
Mice, Knockout
Myeloid Differentiation Factor 88
Proto-Oncogene Proteins / physiology*
Rho Guanine Nucleotide Exchange Factors
Signal Transduction
Up-Regulation
rhoA GTP-Binding Protein / biosynthesis
rhoB GTP-Binding Protein / biosynthesis
rhoB GTP-Binding Protein / physiology*

Substances

Adaptor Proteins, Signal Transducing
Adaptor Proteins, Vesicular Transport
Arhgef2 protein, mouse
Guanine Nucleotide Exchange Factors
Histocompatibility Antigens Class II
Lipopolysaccharides
Myd88 protein, mouse
Myeloid Differentiation Factor 88
Proto-Oncogene Proteins
Rho Guanine Nucleotide Exchange Factors
TICAM-1 protein, mouse
rhoA GTP-Binding Protein
rhoB GTP-Binding Protein