The FcgammaRIa (CD64) ligand binding chain triggers major histocompatibility complex class II antigen presentation independently of its associated FcR gamma-chain.
Within multi-subunit Ig receptors, the FcR gamma-chain immunoreceptor tyrosine-based activation motif (ITAM) plays a crucial role in enabling antigen presentation. This process involves antigen-capture and targeting to specific degradation and major histocompatibility complex (MHC) class II loading compartments. Antigenic epitopes are then presented by MHC class II molecules to specific T cells. The high-affinity receptor for IgG, hFcgammaRIa, is exclusively expressed on myeloid lineage cells and depends on the FcR gamma-chain for surface expression, efficient ligand binding, and most phagocytic effector functions. However, we show in this report, using the IIA1.6 cell model, that hFcgammaRIa can potentiate MHC class II antigen presentation, independently of a functional FcR gamma-chain ITAM. Immunoelectron microscopic analyses documented hFcgammaRIa alpha-chain/rabbit IgG-Ovalbumin complexes to be internalized and to migrate via sorting endosomes to MHC class II-containing late endosomes. Radical deletion of the hFcgammaRIa alpha-chain cytoplasmic tail did not affect internalization of rabbit IgG-Ovalbumin complexes. Importantly, however, this resulted in diversion of receptor-ligand complexes to the recycling pathway and decreased antigen presentation. These results show the hFcgammaRIa cytoplasmic tail to contain autonomous targeting information for intracellular trafficking of receptor-antigen complexes, although deficient in canonical tyrosine- or dileucine-targeting motifs. This is the first documentation of autonomous targeting by a member of the multichain FcR family that may critically impact the immunoregulatory role proposed for hFcgammaRIa (CD64).
Departments of Immunology and Cell Biology, and Medarex Europe University Hospital Utrecht, Utrecht, The Netherlands.
M J
MJ
van Vugt
M J
MJ
Kleijmeer
T
T
Keler
I
I
Zeelenberg
M A
MA
van Dijk
J H
JH
Leusen
H J
HJ
Geuze
J G
JG
van de Winkel
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D002460:Cell Line; D004705:Endocytosis; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006735:Horseradish Peroxidase; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D051379:Mice; D016253:Microscopy, Immunoelectron; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000276:immunology; D011817:Rabbits; D017452:Receptors, IgG / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D013347:Subcellular Fractions / Q000737:chemistry; D014162:Transfection
D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D010047:Ovalbumin; D006735:Horseradish Peroxidase