SWAP-70 regulates RhoA/RhoB-dependent MHCII surface localization in dendritic cells.
Stimulated dendritic cells (DCs) mature and migrate to lymphoid organs to prime naive T cells. DC maturation augments antigen-presentation capacity of DCs by increasing peptide loading, half-life, and cell surface localization of MHC molecules. Activated SWAP-70(-/-) DCs fail to properly localize MHCII molecules in the plasma membrane, are strongly impaired in T-cell activation, and are altered in F-actin rearrangement. MHCII synthesis, invariant chain removal, and MHCII internalization, however, are unaffected. MHCII surface localization is known to require RhoGTPases. Surprisingly, SWAP70, hitherto known to bind F-actin and Rac, also binds RhoA-GTP. In SWAP-70(-/-) DCs, RhoA and RhoB are stimulus-independent and constitutively active. Surface localization of MHCII molecules and T-cell activation can be restored by blocking RhoA and RhoB before but not during DC activation. Thus, contrasting positive regulation of Rac, SWAP-70 negatively regulates RhoA and-indirectly-RhoB, preventing premature RhoA/RhoB activation. Through RhoA/RhoB regulation, SWAP-70 defines a new pathway to control surface localization of MHCII, a critical element in DC-dependent immune responses.
Ocana-Morgner
Carlos
C
Institute of Physiological Chemistry, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
Wahren
Christine
C
Jessberger
Rolf
R
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006825:Hybridomas; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D015778:Minor Histocompatibility Antigens; D009479:Neuropeptides / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D015854:Up-Regulation / Q000276:immunology; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein; D020743:rhoB GTP-Binding Protein / Q000378:metabolism*
D000954:Antigens, Surface; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D000949:Histocompatibility Antigens Class II; D015778:Minor Histocompatibility Antigens; D009479:Neuropeptides; D009687:Nuclear Proteins; C484602:Rac1 protein, mouse; C113365:Swap70 protein, mouse; C526380:RhoA protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D020743:rhoB GTP-Binding Protein