SWAP-70 regulates RhoA/RhoB-dependent MHCII surface localization in dendritic cells

Blood. 2009 Feb 12;113(7):1474-82. doi: 10.1182/blood-2008-04-152587. Epub 2008 Sep 18.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Surface / metabolism
  • Bone Marrow Cells / cytology
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Histocompatibility Antigens Class II / metabolism*
  • Hybridomas
  • Mice
  • Mice, Inbred BALB C
  • Mice, Mutant Strains
  • Minor Histocompatibility Antigens
  • Neuropeptides / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Spleen / cytology
  • Up-Regulation / immunology
  • rac GTP-Binding Proteins / metabolism
  • rac1 GTP-Binding Protein
  • rho GTP-Binding Proteins / metabolism*
  • rhoA GTP-Binding Protein
  • rhoB GTP-Binding Protein / metabolism*

Substances

  • Antigens, Surface
  • DNA-Binding Proteins
  • Guanine Nucleotide Exchange Factors
  • Histocompatibility Antigens Class II
  • Minor Histocompatibility Antigens
  • Neuropeptides
  • Nuclear Proteins
  • Rac1 protein, mouse
  • Swap70 protein, mouse
  • RhoA protein, mouse
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein
  • rhoB GTP-Binding Protein