ITAM signaling in dendritic cells controls T helper cell priming by regulating MHC class II recycling.
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.
Graham
Daniel B
DB
Department of Pathology and Immunology, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA.
Akilesh
Holly M
HM
Gmyrek
Grzegorz B
GB
Piccio
Laura
L
Gilfillan
Susan
S
Sim
Julia
J
Belizaire
Roger
R
Carrero
Javier A
JA
Wang
Yinan
Y
Blaufuss
Gregory S
GS
Sandoval
Gabriel
G
Fujikawa
Keiko
K
Cross
Anne H
AH
Russell
John H
JH
Cella
Marina
M
Swat
Wojciech
W
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D020816:Amino Acid Motifs; D000818:Animals; D017951:Antigen Presentation; D001927:Brain Diseases / Q000139:chemically induced / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004660:Encephalitis; D050031:Hashimoto Disease / Q000139:chemically induced / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology* / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D051567:Proto-Oncogene Proteins c-vav / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology*; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014443:Tyrosine / Q000276:immunology; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; D000949:Histocompatibility Antigens Class II; D051567:Proto-Oncogene Proteins c-vav; D017452:Receptors, IgG; C484963:Tyrobp protein, mouse; D014443:Tyrosine