Cell
Volume 145, Issue 2, 15 April 2011, Pages 268-283
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Article
A Genome-wide Multidimensional RNAi Screen Reveals Pathways Controlling MHC Class II Antigen Presentation

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Summary

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.

Highlights

► Genome-wide screen identifies 276 factors regulating human MHC class II function ► Twenty-one factors identified are associated with autoimmunity ► A CIITA transcriptional feedback loop controlled by TGFβ and RMND5B is defined ► Analysis reveals pathways for MHC class II trafficking and transport in dendritic cells

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These authors contributed equally to this work

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Present address: Genentech, Inc., 1 DNA Way, San Francisco, CA 94080, USA