Author/Authors :
Petra Paul، نويسنده , , Tineke van den Hoorn، نويسنده , , Marlieke L.M. Jongsma، نويسنده , , Mark J. Bakker، نويسنده , , Rutger Hengeveld، نويسنده , , Lennert Janssen، نويسنده , , Peter Cresswell، نويسنده , , David A. Egan، نويسنده , , Marieke van Ham، نويسنده , , Anja ten Brinke، نويسنده , , Hidde L. Ploegh and Huib Ovaa، نويسنده , , Roderick L. Beijersbergen، نويسنده , , Coenraad Kuijl، نويسنده , , Jacques Neefjes، نويسنده ,
Abstract :
MHC class II molecules (MHC-II) present peptides to T helper cells to facilitate immune responses and are strongly linked to autoimmune diseases. To unravel processes controlling MHC-II antigen presentation, we performed a genome-wide flow cytometry-based RNAi screen detecting MHC-II expression and peptide loading followed by additional high-throughput assays. All data sets were integrated to answer two fundamental questions: what regulates tissue-specific MHC-II transcription, and what controls MHC-II transport in dendritic cells? MHC-II transcription was controlled by nine regulators acting in feedback networks with higher-order control by signaling pathways, including TGFβ. MHC-II transport was controlled by the GTPase ARL14/ARF7, which recruits the motor myosin 1E via an effector protein ARF7EP. This complex controls movement of MHC-II vesicles along the actin cytoskeleton in human dendritic cells (DCs). These genome-wide systems analyses have thus identified factors and pathways controlling MHC-II transcription and transport, defining targets for manipulation of MHC-II antigen presentation in infection and autoimmunity.
