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

  1. Daniel B. Graham1,*,
  2. Holly M. Akilesh1,*,
  3. Grzegorz B. Gmyrek1,
  4. Laura Piccio2,
  5. Susan Gilfillan1,
  6. Julia Sim3,
  7. Roger Belizaire1,
  8. Javier A. Carrero1,
  9. Yinan Wang1,
  10. Gregory S. Blaufuss1,
  11. Gabriel Sandoval1,
  12. Keiko Fujikawa4,
  13. Anne H. Cross2,
  14. John H. Russell3,
  15. Marina Cella1, and
  16. Wojciech Swat1
  1. Departments of 1Pathology and Immunology,
  2. 2Neurology and Neurosurgery, and
  3. 3Developmental Biology, Washington University School of Medicine, St Louis, MO; and
  4. 4Department of Pathology and Immunology, Hokkaido University School of Medicine, Sapporo, Japan

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.

  • Submitted October 20, 2009.
  • Accepted May 31, 2010.
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