Autophagy and proteasome interconnect to coordinate cross-presentation through MHC class I pathway in B cells

Immunol Cell Biol. 2016 Nov;94(10):964-974. doi: 10.1038/icb.2016.59. Epub 2016 Jun 14.

Abstract

Cross-presentation of exogenous protein antigens by B cells through the major histocompatibility complex (MHC) class I pathway in lymphoid malignancies, and transplant setting has been recognised as an important mediator of immune pathogenesis and T cell-mediated immune regulation. However, the precise mechanism of cross-presentation of exogenous antigens in B cells has remained unresolved. Here we have delineated a novel pathway for cross-presentation in B cells, which involves synergistic cooperation of the proteasome and autophagy. After endocytosis, protein antigen is processed through an autophagy- and proteasome-dependent pathway and CD8+ T-cell epitopes are loaded onto MHC class I molecules within the autophagolysomal compartment rather than the conventional secretory pathway, which requires transporters associated with antigen processing-dependent transport. Interestingly, this cross-presentation was critically dependent on valosin-containing protein (VCP)/p97 ATPase through its participation in autophagy. Loss of VCP/p97 ATPase was coincident with accumulation of LC3-II and marked reduction in antigen presentation. These observations provide unique insight on how the autophagy and proteasomal degradation systems interconnect to coordinate MHC class I-restricted cross-presentation in B cells.

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism
  • Adenosine Triphosphate / pharmacology
  • Autophagy / drug effects
  • Autophagy / immunology*
  • Autophagy-Related Proteins / metabolism
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Cross-Priming / drug effects
  • Cross-Priming / immunology*
  • Cytomegalovirus / metabolism
  • Epitopes, T-Lymphocyte / metabolism
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Proteasome Endopeptidase Complex / metabolism*
  • Valosin Containing Protein / metabolism
  • Viral Proteins / metabolism

Substances

  • ATP-Binding Cassette Transporters
  • Autophagy-Related Proteins
  • Epitopes, T-Lymphocyte
  • Histocompatibility Antigens Class I
  • Viral Proteins
  • transporter associated with antigen processing (TAP)
  • Adenosine Triphosphate
  • Proteasome Endopeptidase Complex
  • Valosin Containing Protein