ITAM signaling in dendritic cells controls T helper cell priming by regulating MHC class II recycling.

Blood
Daniel B GrahamWojciech Swat

Abstract

Immature dendritic cells (DCs) specialize in antigen capture and maintain a highly dynamic pool of intracellular major histocompatibility complex class II (MHCII) that continuously recycles from peptide loading compartments to the plasma membrane and back again. This process facilitates sampling of environmental antigens for presentation to T helper cells. Here, we show that a signaling pathway mediated by the DC immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptors (DAP12 and FcRγ) and Vav family guanine nucleotide exchange factors controls the half-life of surface peptide-MHCII (pMHCII) complexes and is critical for CD4 T-cell triggering in vitro. Strikingly, mice with disrupted DC ITAMs show defective T helper cell priming in vivo and are protected from experimental autoimmune encephalitis. Mechanistically, we show that deficiency in ITAM signaling results in increased pMHCII internalization, impaired recycling, and an accumulation of ubiquitinated MHCII species that are prematurely degraded in lysosomes. We propose a novel mechanism for control of T helper cell priming.

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Citations

Feb 9, 2013·International Immunology·Bettina JuxWaldemar Kolanus
May 4, 2012·Immunology Letters·Marcello Albanesi, Marc Daëron
Feb 26, 2013·European Journal of Immunology·Grzegorz B GmyrekWojciech Swat
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Jul 29, 2009·PLoS Biology·Fiona J CulleyDaniel M Davis
Sep 25, 2014·Immunology·Lc BonifazFj Sánchez-García
Feb 26, 2020·Proceedings of the National Academy of Sciences of the United States of America·Hsueh Chung LuJianrong Li

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