Skip to main content

Towards understanding and manipulation of MHC class II antigen presentation

Objective

MHC class II molecules are crucial for specific immune responses. In a complicated series of cell biological events, they catch a peptide in the endosomal route for presentation at the plasma membrane to the immune system. At present some 20 factors have been identified as involved in the process of MHC class II antigen presentation that are potential targets for manipulating these responses as MHC class II molecules are involved in most auto-immune diseases. Defining further targets for manipulating MHC class II responses would have implications for various disease states when these can be inhibited by chemical compounds or biologicals. We have performed a genome-wide FACS-based siRNA screen for molecules affecting MHC class II expression and peptide loading. After 100.000 individual 2-color FACS analyses, we identified 276 proteins that can be functionally sub-clustered for expression and for cell biological effects. We now propose to study the cell biology of these 276 hits to elucidate the molecular and cell biological mechanisms of MHC class II antigen presentation (the MHC class II-ome). As a first step, the 276 hits are sub-clustered for effects on MHC class II transcription or cell biology. These sub-clusters may correspond to networks. We propose to validate and extend these networks by experiments by a team of scientists concentrating on the various aspects of the cell biology of MHC class II antigen presentation. A parallel chemical compound screen will be performed to identify compounds affecting MHC class II antigen presentation. By cross-correlating the biological phenotypes of compounds with those of siRNA silencing, novel target-lead combinations will be defined by reciprocal chemical genetics. Our experiments should result in a global understanding of MHC class II antigen presentation. In addition, it should reveal target-lead combinations for manipulation of MHC class II antigen presentation in infection, auto-immune disease and transplantation.

Field of science

  • /natural sciences/biological sciences/cell biology
  • /medical and health sciences/clinical medicine/transplantation
  • /natural sciences/biological sciences/genetics and heredity
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /medical and health sciences/basic medicine/immunology

Call for proposal

ERC-2009-AdG
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Address
Plesmanlaan 121
1066 CX Amsterdam
Netherlands
Activity type
Research Organisations
EU contribution
€ 2 112 300
Principal investigator
Jacobus Jozef Cornelis Neefjes (Prof.)
Administrative Contact
Henri Van Luenen (Dr.)

Beneficiaries (1)

STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Netherlands
EU contribution
€ 2 112 300
Address
Plesmanlaan 121
1066 CX Amsterdam
Activity type
Research Organisations
Principal investigator
Jacobus Jozef Cornelis Neefjes (Prof.)
Administrative Contact
Henri Van Luenen (Dr.)