Review Article | Published:

Fcγ receptors as regulators of immune responses

Nature Reviews Immunology volume 8, pages 3447 (2008) | Download Citation

Abstract

In addition to their role in binding antigen, antibodies can regulate immune responses through interacting with Fc receptors (FcRs). In recent years, significant progress has been made in understanding the mechanisms that regulate the activity of IgG antibodies in vivo. In this Review, we discuss recent studies addressing the multifaceted roles of FcRs for IgG (FcγRs) in the immune system and how this knowledge could be translated into novel therapeutic strategies to treat human autoimmune, infectious or malignant diseases.

Key points

  • The family of Fc receptors for IgG (FcγRs) is broadly expressed by cells of haematopoietic origin and consists of one inhibitory and several activating receptors that differ in their affinity and specificity for immunoglobulin subclasses.

  • On innate immune effector cells, activating and inhibitory FcγRs set a threshold for cell activation by immune complexes. Important examples for effector responses that are regulated by FcγRs are phagocytosis, ADCC and the release of inflammatory mediators.

  • On dendritic cells (DCs), paired FcγR expression regulates cell maturation and antigen presentation, thereby indirectly controlling the cellular immune response.

  • On B cells, the inhibitory FcγRIIB is essential for the maintenance of humoral tolerance. It acts as a late checkpoint at the level of class-switched memory B cells, plasmablasts or plasma cells. In addition, FcγRIIB has an important role in regulating plasma-cell homeostasis and survival.

  • The antibody–FcγR interaction is influenced by several factors that have an impact on the expression level of activating and inhibitory FcγRs (such as cytokines) or change the affinity of the antibody–FcγR interaction (such as differential antibody glycosylation).

  • Depending on the specific glycosylation pattern, IgG molecules can have enhanced pro- or anti-inflammatory activities. Importantly, antibody glycosylation is regulated during immune responses.

  • Targeting the factors that influence the antibody–FcγR interaction might open new avenues for immunotherapeutic interventions in autoimmune and malignant diseases.

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Acknowledgements

We would especially like to thank P. Sondermann (Roche), who generously provided the structural data and pictures concerning the antibody FcR interaction and for his critical reading of the manuscript. Similarly, we thank. S. Bolland for suggestions on the manuscript. This work was supported by grants from the German Research Foundation (DFG) and the Bavarian Genome Network (BayGene) to F.N., and by grants from the National Institutes of Health (NIH), USA, and E. Ludwig to J.V.R. We apologize to all colleagues whose important work was not directly cited due to space limitations. These references can be found in the numerous review articles referred to in this Review.

Author information

Affiliations

  1. Laboratory of Experimental Immunology and Immunotherapy, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen-Nuremberg, Glueckstr. 6, 91054 Erlangen, Germany.  fnimmerj@molmed.uni-erlangen.de

    • Falk Nimmerjahn
  2. Laboratory for Molecular Genetics and Immunology, Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.  ravetch@mail.rockefeller.edu

    • Jeffrey V. Ravetch

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Glossary

Regulatory T cells

A T cell subset that is capable of suppressing the activity of other antigen-specific T cells including autoreactive T cells. Depletion of regulatory T cells results in the loss of peripheral tolerance and the development of autoimmune disease.

Immunoreceptor tyrosine-based activation motif

(ITAM). A short peptide motif containing tyrosine residues that is found in the cytoplasmic tail of several signalling adaptor proteins such as the common γ- or CD3ζ-chain. It is necessary to recruit proteins that are involved in triggering activating signalling proteins. The consensus sequence is Tyr-X-X-(Leu/Ile)-X6–8-Tyr-X-X-(Leu/Ile), where X denotes any amino acid.

Immunoreceptor tyrosine-based inhibitory motif

(ITIM). A short peptide motif containing a tyrosine residue that is found in the cytoplasmic portion of FcγRIIB and other regulatory proteins such as CD22 or CD72 that is necessary to recruit negative regulatory signalling proteins. The consensus sequence is (Ile/Val/Leu/Ser)-X-Tyr-X-X-(Leu/Val), where X denotes any amino acid.

Type I transmembrane glycoproteins

Glycoproteins of which the carboxyterminus of the polypeptide chain is located in the cytosol whereas the aminoterminus is exposed to the extracelluar space.

Neonatal FcR

(FcRn). FcRn is unrelated to classical FcRs and binds to a different region in the antibody Fc fragment. Structurally it is related to the family of MHC class I molecules and is responsible for regulating IgG half-life.

Dyad symmetry

The symmetrical arrangement of the repetitive structural elements an antibody molecule is composed of.

Complement cascade

There are three independent pathways that can lead to the activation of the complement cascade. The classical pathway is activated via C1q binding to immune complexes, the alternative pathway is triggered by direct C3 activation, and the lectin pathway is initiated by mannose-binding lectin (MBL) binding to the surface of microorganisms.

K/BxN serum transfer arthritis model

A mouse strain formed by crossing non-obese diabetic (NOD)/Lt mice with KRN T-cell-receptor-transgenic mice on the C57BL/6 background. As the KRN receptor on the T cells recognizes a peptide from the autoantigen glucose-6-phosphate isomerase, these mice develop an arthritis that is mediated, and transferable, by circulating antibody against glucose-6-phosphate isomerase.

Class switching

If B cells recognize their cognate antigen in the spleen a portion of them switch the expression of their B-cell receptor from IgM to other isotypes such as IgG, IgA or IgE. The decision of which isotype is generated is strongly influenced by the specific cytokine milieu and other cells such as T-helper cells.

Pleckstrin homology (PH)-domain

An amino acid motif that enables proteins to recognize phosphatidylinositol-3,4,5-trisphosphate.

Plasmablasts

A short lived, dividing cell population that can develop from any type of activated B cell and that is characterized by its capacity to secrete antibodies.

Plasma cells

Terminally differentiated quiescent B cells that develop from plasmablasts and are characterized by their capacity to secrete large amounts of antibodies.

Affinity maturation

A process in which random mutations are introduced into the variable regions of the B-cell receptor genes followed by selection of cells with a higher affinity for the cognate antigen. This process takes place in specialized compartments of the spleen, which are known as germinal centres.

Competitive dislocation

This term refers to the competition of newly developed plasma cells for anatomical niches in the bone marrow that are already occupied by plasma cells that were generated during previous immune responses.

Cross presentation

The uptake of proteins by dendritic cells results in their degradation into small peptides in endosomal and lysosomal compartments and peptide presentation on MHC class II molecules. Cross presentation describes a process in which endocytosed material escapes into the cytoplasm where it is degraded by the proteasome followed by presentation on MHC class I molecules.

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DOI

https://doi.org/10.1038/nri2206

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