Third Party Funds Group - Sub project
Acronym: GRK 2599 FAIR P04
Start date : 01.01.2021
End date : 30.07.2025
Dendritic cells (DCs) are essential for orchestrating both tolerogenic and protective adaptive immune responses. They achieve this by binding of antigens followed by antigen internalization, processing, and finally presentation to T cells in a DC subtype-dependent manner. In this respect, two subsets of DCs can be distinguished in the spleen of mice: CD8+ conventional DCs (cDC1) that predomi-nantly initiate CD8+ T cell responses and CD8- cDCs (cDC2) that preferentially induce CD4+ T cell responses (Dudziak et al., 2007). Antigen recognition can be mediated by canonical type I Fc recep-tors (FcRs) broadly expressed on both DC subsets and by select C-type lectin receptors. These include DEC205 or Clec9a present on cDC1 and DCIR2 on cDC2 (Lehmann et al. 2017*). Apart from classical FcRs, specific C-type lectin receptors were shown to recognize IgG and have been termed type II FcRs (Pincetic et al. 2014*, own unpublished observations). Antigen uptake, as well as subsequent DC maturation, is enhanced when the antigen was delivered in a complex with IgG, i.e., an immune complex (IC) (Regnault et al. 1999*). Major determinants of IgG binding to Fc recep-tors are the IgG subclass and the composition of the glycan attached to the Fc domain of IgG. Con-cerning subclass specificity of type I Fc receptors, IgG1 antibodies display a higher affinity to the inhibitory FcγRIIB while IgG2a/c and IgG2b preferentially interact with activating FcγRI, FcγRIII and FcγRIV (Kao et al. 2015). When we previously characterized IgG subclass-specific glycosylation, we further found IgG1 to be predominantly in the pro-inflammatory agalactosylated form while IgG2b and IgG2c contained high levels of galactose, fucose and terminal sialic acid (Kao et al. 2017). Es-pecially terminal sialylation was previously shown to enhance the anti-inflammatory capacity of IgG by shifting IgG binding from activating classical FcγRs to type II Fc receptors (Kaneko et al. 2006*, Pincetic et al. 2014*). These findings suggest that IgG-containing immune complexes can modulate the activity and subsequent antigen-presenting ability of DCs. Thus, this project aims to investigate how IgG immune complexes of different subclasses and with distinct Fc glycosylation patterns fine-tune DC activation via type I and type II FcRs and to decipher the role of individual Fc receptors.