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RI-Targeted Antigen With Class I MHC: Implications for Antigen Processing1
Departments of
*
Physiology and
Microbiology, Dartmouth Medical School, Lebanon, NH 03756
The high-affinity receptor for IgG (CD64 or Fc
RI) is
constitutively expressed exclusively on professional APCs (monocytes,
macrophages, and dendritic cells). When Ag is targeted specifically to
FcRI, Ag presentation is markedly enhanced, although the mechanism
of this enhancement is unknown. In an effort to elucidate the pathways
involved in FcRI targeting, we developed a model targeted Ag using
enhanced green fluorescent protein (eGFP). This molecule, wH22xeGFP,
consists of the entire humanized anti-FcRI mAb H22 with eGFP
genetically fused to the C-terminal end of each CH3 domain. wH22xeGFP
binds within the ligand-binding region by its Fc end, as well as
outside the ligand-binding region by its Fab ends, thereby
cross-linking FcRI. Confocal microscopy studies revealed that
wH22xeGFP was rapidly internalized by the high-FcRI-expressing cell
line U937 10.6, but did not associate with intracellular proteins Rab4,
Rab5a, or Lamp-1, suggesting that the targeted fusion protein was not
localized in early endosomes, recycling vesicles, or lysosomes.
Interestingly, wH22xeGFP was found colocalized with intracellular MHC
class I, suggesting that FcRI-targeted Ags may converge upon a class
I processing pathway. These data are in agreement with studies in the
mouse showing that FcRI targeting can lead to Ag-specific activation
of cytotoxic T cells. Data obtained from these studies should lead to a
better understanding of how Ags targeted to FcRI are processed and
under what conditions they lead to presentation of antigenic peptides
in MHC class I, as a foundation for the use of FcRI-targeted Ags as
vaccines.
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