title: TRIF-GEFH1-RhoB pathway is involved in MHCII expression on dendritic cells that is critical for CD4 T-cell activation.
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.
authors.affiliation: Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Hokuto
authors.initials: H
authors.lastname: Kamon
authors.forename: Takaya
authors.initials: T
authors.lastname: Kawabe
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Kitamura
authors.forename: Jihye
authors.initials: J
authors.lastname: Lee
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kamimura
authors.forename: Tsuneyasu
authors.initials: T
authors.lastname: Kaisho
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Akihiro
authors.initials: A
authors.lastname: Iwamatsu
authors.forename: Hisashi
authors.initials: H
authors.lastname: Koga
authors.forename: Masaaki
authors.initials: M
authors.lastname: Murakami
authors.forename: Toshio
authors.initials: T
authors.lastname: Hirano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000502:physiology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D015854:Up-Regulation; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis; D020743:rhoB GTP-Binding Protein / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D020662:Guanine Nucleotide Exchange Factors; D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D011518:Proto-Oncogene Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D020742:rhoA GTP-Binding Protein; D020743:rhoB GTP-Binding Protein; C577402:Arhgef2 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse