Key receptors for adaptive immunity

Uptake, processing, and presentation of antigens, followed by activation of T cells, are key processes in adaptive immunity. T cells need to first take up the antigen, process the antigen, and then present it on the MHC molecule on the cell surface. A critical step in antigen presentation is the transport of the foreign cargo to the intracellular compartment, where the antigen can be processed and loaded onto the MHC molecule. FcγR plays an important role in antigen uptake, processing, and presentation.

FcγR识别IgG Fc段，从而识别Ig-IC（immune complexes，免疫复合物）。

六类FcγR（Nat Rev Immunol . 2020 Oct; 20(10):633-643）

Presents immune complexes

1. Ig-IC binds low-affinity FcγR on the surface of APC,
2. Activated FcγRs cross-linking, resulting in ITAM phosphorylation and clathrin-mediated endocytosis of FcγR:IgG-IC aggregates, followed by IgG-IC transport to lysosomes
3. Within lysosomes, FcγRs and endocytic antigens are degraded by proteases and eventually loaded into MHCII-like complexes, a process that relies on cathepsin and HLA-DM activity
4. Yellow arrows: Non-"self" antigens internalized by FcγR cross-linking during cross-presentation can also be delivered into the cytoplasm, where they are processed similarly to endogenous proteins. The resulting 9-10-aa long peptide will be incorporated into the MHCI-like protein complex.

The origin of the nomenclature of the FcRn transport antigen neonatal Fc receptor (FcRn): FcRn rats transfer IgG across the intestinal epithelium from the mother to the offspring, and in humans IgG is transferred from the mother to the offspring. However, FcRn expression is not limited to neonates. In adults, FcRn plays a key role in maintaining IgG levels and IgG transport across the epithelial barrier. At the intestinal epithelial barrier, human FcRn can transport IgG to the lumen to bind to homologous antigens and recover IgG-ICs across the intestinal barrier for subsequent uptake by mucosal DCs. FcRn mainly circulates between the endosomal compartment and the plasma membrane. At the low pH of the intracellular body cavity, FcRn binds to IgG with high affinity, and then releases IgG to the cell surface at neutral pH, thereby preventing IgG from being destroyed by intracellular lysosomes and prolonging the half-life of circulating IgG molecules.

1. In the gut, IgG antibodies can bind to FcRn expressed on the basal side of the epithelial cell membrane. These antibodies will be endocytosed and bind to FcRn with high affinity in the acidic microenvironment of the endosome.
2. On the villous surface of epithelial cells (lumen side), FcRn has a reduced affinity for IgG due to a more neutral pH, and these IgG antibodies are released, binding to soluble protein antigens. Alternatively, (orange arrows), FcRn can return monomeric IgGs to the interstitium (IgG recovery), a process that prevents IgG degradation in acidic compartments, especially in APCs.
3. The intestinal lumen Ig-IC binds to FcRn and is endocytosed, passing through endosomal vesicles and across epithelial cells.
4. On the basal side, Ig-IC is released, after which it is recognized, endocytosed, processed, and antigen presented by FcγR on the surface of APC cells.

Antigen presentation and T cell activation

1. IgG-IC mediates binding to low-affinity FcγRs, and activation of cross-linking leads to src kinase-mediated phosphorylation of ITAM, inducing activation of downstream-specific kinases (lyn, syk), ultimately leading to PI3K activation, increased intracellular calcium, and cellular activation. Intracellularly in FcγRIIB is an immunosuppressive motif (ITIM), and the corresponding signal inhibits cell activation.
2. Cellular activation triggers transcriptional programs within APCs, enhances the expression of pro-inflammatory cytokines (e.g., IL-6, IL-15, IL-10), and upregulates membrane-bound co-activating molecules, including CD80 and CD86.
3. MHCII-antigen peptide-TCR leads to T cell activation, which in turn enhances T cell activation through CD28-CD80/CD86 co-stimulation signals.

FcγR variants

Various genetic variants in FcγR affect its affinity and interaction with different IgG isotypes, related to disease and the clinical potential of therapeutic antibodies.

SLE is a chronic autoimmune disease characterized by damage to various organs, such as the skin and kidneys (lupus nephritis), which often leads to serious clinical complications. SLE-associated susceptibility genes include the FcγR locus on chromosome 1q23 (including FcγRII and FcγRIII). Among the inhibitory FcgRIIB, the single amino acid polymorphism FcγRIIBT232 was first identified in Japanese SLE patients. This polymorphism, 695T>C, results in a non-synonymous surrogate mutation Ile232Thr (I232T) within the FcγRII transmembrane domain. FcgRIIBT232 mutations may lead to a failure to activate inhibitory FcγRs, which in turn promotes a pro-inflammatory response in ICs and enhances autoantibody production. In addition to this, a number of other mutations have also been reported.

brief summary

The FcγR family provides a critical control point for the regulation of antigen presentation of IgG-coated antigens. This control can be implemented in several stages, such as the internalization of antigens, the transport of antigens within cells, and by controlling subsequent signaling events that lead to antigen presentation. The stimulus or inhibition signal generated by FcγR leads to the regulation of costimulatory molecules and cytokines, which further modulates the response to antigens. The increasing number of FcγR genetic variants found underscores the importance of these pathways for human disease.

Featured References

1. Junker F, Gordon J and Qureshi O (2020) Fc Gamma Receptors and Their Role in Antigen Uptake, Presentation, and T Cell Activation.Front. Immunol. 11:1393
2. Kerntke C, Nimmerjahn F, Biburger M. There is (Scientific) strength in numbers: a comprehensive quantitation of Fc gamma receptor numbers on human and murine peripheral blood leukocytes. Front Immunol. (2020) 11:118.

3. Dalby E, Christensen SM, Wang J, Hamidzadeh K, Chandrasekaran P, Hughitt VK, et al. Immune complex–driven generation of human macrophages with anti-inflammatory and growth-promoting activity. J Immunol. (2020) 204:1901382.

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