Peripheral blood dendritic cells express Fc epsilon RI as a complex composed of Fc epsilon RI alpha- and Fc epsilon RI gamma-chains and can use this receptor for IgE-mediated allergen presentation.

Abstract

Originally limited to basophils and mast cells, the spectrum of high affinity IgE receptor (Fc epsilon RI-bearing cells has expanded recently to include Langerhans cells, dermal dendritic cells (DC), monocytes, and eosinophils. As a result of studies on the distribution, structure, and function of Fc epsilon RI on APCs, we discovered a minor nonbasophil, nonmonocyte PBMC population that can bind IgE via Fc epsilon RI. This receptor occurs on the surface of these cells as a multimeric structure containing Fc epsilon RI alpha- and Fc epsilon RI gamma-chains but, unlike its counterpart on basophils, lacking Fc epsilon RI beta. Further experiments revealed that these Fc epsilon RI alpha gamma-expressing cells closely resemble peripheral blood DC by immunophenotype (HLA-DRhigh, HLA-DQhhigh; CD4+, CD11a+, CD32+, CD33+, B7/2 (CD86)+; CD11blow, CD14low, CD40low, CD54low, CD64low) and cell morphology. These features allowed us to isolate Fc epsilon RI-expressing DC from the peripheral blood and to investigate their immunostimulatory properties. We found Fc epsilon RI-positive DC to be efficient stimulators of both primary (allogeneic MLR) and Fc epsilon RI/IgE-dependent, secondary T cell responses at low cell numbers. Thus, Fc epsilon RI-expressing DC may not only amplify established type I allergic immune reactions but, unlike Fc epsilon RI-positive semiprofessional APCs, may be able to prime naive T cells to common and/or cryptic epitopes of IgE-reactive Ags.

Identification of redundancy between human FcεRIβ and MS4A6A proteins points toward additional complex mechanisms for FcεRI trafficking and signaling

“…In humans and mice, FcεRI are expressed exclusively in MCs and basophils as tetrameric complexes containing the FcεRIβ subunits. [20][21][22][23] However, in humans, FcεRI also exists as trimeric complexes lacking FcεRIβ which are expressed on several cell types, [23][24][25][26][27][28][29][30][31] whereas mice do not express the trimeric form, at least under non-inflammatory conditions. 20,32,33 Therefore, FcεRIβ may be less…”

“…Due to the highly homologous sequence of MS4A6A and FcεRIβ and the similar localization within the cell for the alternative isoforms, we predicted that MS4A6A could traffic FcεRI to the plasma membrane and act as an FcεRIβ-like protein, exhibiting redundancy between the two proteins. We began to test this hypothesis by validating an antibody for MS4A6A and utilizing gene targeting using shRNA and lentiviral delivery as we have performed for other MS4A proteins (2,26). We performed transfections with the EGFP fusion constructs for full length FcεRIβ and MS4A6A that we generated from cloning in HLMCs (Figure 3), into LAD2 cells and assessed expression with flow cytometry (Figure 4A,B).…”

“…In humans and mice, FcεRI are expressed exclusively in MCs and basophils as tetrameric complexes containing the FcεRIβ subunits 20–23 . However, in humans, FcεRI also exists as trimeric complexes lacking FcεRIβ which are expressed on several cell types, 23–31 whereas mice do not express the trimeric form, at least under non‐inflammatory conditions 20,32,33 . Therefore, FcεRIβ may be less critical for FcεRI trafficking in humans and trimeric FcεRI could account for the lack of translation of FcεRIβ SSOs that we have observed 19 .…”

On the complexity of IgE: The role of structural flexibility and glycosylation for binding its receptors

“…In contrast, in humans, FcεRI can also exist as a trimeric structure, lacking the β-chain, and is expressed on antigen-presenting cells such as dendritic cells ( 44 ), monocytes ( 45 ), and Langerhans cells ( 46 , 47 ). These cells utilize the trimeric isoform of FcεRI for the uptake of antigens via IgE, which is then transported to endo/lysosomal compartments for loading and presentation on MHC class II molecules ( 44 , 48 , 49 ).…”

“…The role of antigen presentation by the FcεRI in allergy is not clear. Some studies show that antigen uptake by the FcεRI leads to a T H 2 response and thus may be responsible for initiating allergic reactions ( 44 , 59 ). In contrast, other studies show that antigen presentation by FcεRI has a positive, allergy-reducing effect ( 135 , 136 ).…”