CD9 Regulates Major Histocompatibility Complex Class II Trafficking in Monocyte-Derived Dendritic Cells

Mol Cell Biol. 2017 Jul 14;37(15):e00202-17. doi: 10.1128/MCB.00202-17. Print 2017 Aug 1.

Abstract

Antigen presentation by dendritic cells (DCs) stimulates naive CD4+ T cells, triggering T cell activation and the adaptive arm of the immune response. Newly synthesized major histocompatibility complex class II (MHC-II) molecules accumulate at MHC-II-enriched endosomal compartments and are transported to the plasma membrane of DCs after binding to antigenic peptides to enable antigen presentation. In DCs, MHC-II molecules are included in tetraspanin-enriched microdomains (TEMs). However, the role of tetraspanin CD9 in these processes remains largely undefined. Here, we show that CD9 regulates the T cell-stimulatory capacity of granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent bone marrow-derived DCs (BMDCs), without affecting antigen presentation by fms-like tyrosine kinase 3 ligand (Flt3L)-dependent BMDCs. CD9 knockout (KO) GM-CSF-dependent BMDCs, which resemble monocyte-derived DCs (MoDCs), induce lower levels of T cell activation than wild-type DCs, and this effect is related to a reduction in MHC-II surface expression in CD9-deficient MoDCs. Importantly, MHC-II targeting to the plasma membrane is largely impaired in immature CD9 KO MoDCs, in which MHC-II remains arrested in acidic intracellular compartments enriched in LAMP-1 (lysosome-associated membrane protein 1), and MHC-II internalization is also blocked. Moreover, CD9 participates in MHC-II trafficking in mature MoDCs, regulating its endocytosis and recycling. Our results demonstrate that the tetraspanin CD9 specifically regulates antigenic presentation in MoDCs through the regulation of MHC-II intracellular trafficking.

Keywords: CD9; MHC-II; antigen presentation; monocyte-derived dendritic cells; tetraspanin-enriched microdomain.

MeSH terms

  • Animals
  • Antigen Presentation
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Movement
  • Cells, Cultured
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Gene Deletion
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology
  • Histocompatibility Antigens Class II / immunology*
  • Histocompatibility Antigens Class II / metabolism
  • Lymphocyte Activation
  • Membrane Proteins / immunology
  • Mice, Inbred C57BL
  • Monocytes / cytology
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Protein Transport
  • Tetraspanin 29 / genetics
  • Tetraspanin 29 / immunology*

Substances

  • Histocompatibility Antigens Class II
  • Membrane Proteins
  • Tetraspanin 29
  • flt3 ligand protein
  • Granulocyte-Macrophage Colony-Stimulating Factor