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Fcγ Receptors As Regulators of Immune Responses

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Fcγ Receptors As Regulators of Immune Responses REVIEWS Fcγ receptors as regulators of immune responses Falk Nimmerjahn* and Jeffrey V. Ravetch‡ 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. Regulatory T cells A productive immune response results from the effec- of antigenic peptides that are presented on the surface A T cell subset that is capable tive integration of positive and negative signals that of DCs to cytotoxic T cells, T helper cells, and regulatory of suppressing the activity have an impact on both innate and adaptive immune T cells. Thus, FcγRs are involved in regulating a multitude of other antigen-specific T cells cells. When positive signals dominate, cell activation of innate and adaptive immune responses, which makes including autoreactive T cells. Depletion of regulatory and pro-inflammatory responses ensue, resulting in the them attractive targets for the development of novel T cells results in the loss of elimination of pathogenic microorganisms and viruses. immunotherapeutic approaches (FIG. 1). peripheral tolerance and the In the absence of such productive stimulation, cell activa- In this Review, we summarize our current under- development of autoimmune tion is blocked and active anti-inflammatory responses standing of the role of different members of the FcγR disease. can occur. Modulation of this binary system occurs family in regulating immune responses. Our focus is through the action of cytokines, downstream signal- largely based on results obtained in mouse knockout ling pathways and cell–cell contact. The perturbation of model systems and genetic linkage and association these thresholds can result in aberrant responses that are studies in human patients with autoimmune disease or either insufficient to deal with pathogenic microorgan- cancer. Moreover, we address recent insights into how isms or result in the loss of tolerance and the induction differential antibody glycosylation influences FcγR bind- of autoimmune responses. The family of Fc receptors ing and the maintenance of an anti-inflammatory envi- (FcRs) for IgG (FcγRs) provides a prime example of how ronment during the steady state. Finally, we will discuss simultaneous triggering of activating and inhibitory how these results might be useful for improving human signalling pathways sets thresholds for cell activation immunotherapy and how predictions can be tested in 1 *Laboratory of Experimental and thus generates a well-balanced immune response . novel humanized mouse models. Immunology and Indeed, in a variety of human autoimmune diseases, such Immunotherapy, Nikolaus- as arthritis and systemic lupus erythematosus (SLE), The family of Fcγ receptors Fiebiger-Center for Molecular aberrant expression or the presence of allelic variants of To date, four different classes of FcγRs, known as Medicine, University of Erlangen-Nuremberg, FcγRs with altered functionality have been observed that FcγRI, FcγRIIB, FcγRIII and FcγRIV, have been rec- 2 Glueckstr. 6, 91054 Erlangen, contribute to the pathogenesis of these diseases . In addi- ognized in mice (FIG. 2). Orthologous proteins corre- Germany. tion to their well-defined roles in triggering activation sponding to the mouse FcγRs have been identified in ‡Laboratory for Molecular of innate effector cells, FcγRs function in antigen pres- other mammalian species. In humans, monkeys and Genetics and Immunology, Rockefeller University, 1230 entation and immune-complex-mediated maturation mice, most of the corresponding genes are clustered in York Avenue, New York, of dendritic cells (DCs), and in the regulation of B-cell close proximity on chromosome 1 next to the family of New York 10021, USA. activation and plasma-cell survival3. Thus, FcγRs not only FcR homologous genes4. The human and primate FcγR e-mails: fnimmerj@molmed. control innate immune effector cell activation but are also systems are the most complex, as is exemplified by the uni-erlangen.de; involved in regulating the production and specificity of existence of an FcγRI gene family (which includes [email protected] doi:10.1038/nri2206 their ligands (that is, antibodies). Moreover, by regulat- Fcgria, Fcgrib and Fcgric) and an FcγRII gene family Published online ing DC activity, FcγRs control whether an immunogenic (which includes Fcgriia and Fcgriic) and the presence 7 December 2007 or tolerogenic response is initiated after the recognition of several allelic FcγR variants5 (FIG. 2). Based on the 34 | JANUarY 2008 | volUme 8 www.nature.com/reviews/immunol © 2008 Nature Publishing Group REVIEWS • Release of chemoattractants • Release of cytotoxic substances • Release of vasoactive substances • Phagocytosis • Release of chemoattractants Neutrophil Mast cell Basophil • Oxidative burst Monocyte or • Cytotoxicity macrophage • Release of pro-inflammatory mediators • Modulation of cell activation • Antigen presentation (T cells and B cells) Immune • Regulation of peripheral tolerance complex Antigen Antibody TReg cell CD8+ T cell Dendritic cell CD4+ T cell B cell Plasma cell • Modulation of cell • Apoptosis activation Activating Inhibitory • Shaping the B-cell FcR FcR repertoire Figure 1 | Regulatory functions of immune complexes. Immune complexes bind to activating Fc receptors (FcR) and inhibitory FcRs that are expressed by innate immune effector cells such as basophils, mast cells,Na turneutrophils,e Reviews |monocytes Immunolog y and macrophages, in which they trigger the indicated effector responses. Binding of immune complexes to FcRs on dendritic cells results in phagocytosis and presentation of antigenic peptides on MHC class I and class II molecules. + + Antigen-specific CD8 cytotoxic T cells, CD4 helper T cells or regulatory T cells (TReg cells) that recognize these peptide– MHC complexes become activated and mediate various effector functions such as killing of virus-infected cells, modulation of immune responses or providing T-cell help for antigen-specific B cells. B cells only express the inhibitory low-affinity FcR for IgG (FcγRIIB), which regulates activating signals transduced by the B-cell receptor (BCR). On plasma cells, which produce high levels of antigen-specific antibodies, BCR expression is very low or absent, resulting in exclusive triggering of inhibitory signalling pathways. genomic localization and sequence similarity in the significantly lower compared with their mouse coun- extracellular portion, mouse FcγRIV seems to be the terparts. Nonetheless, results obtained in mouse model orthologue of human FcγRIIIA, and mouse FcγRIII is systems have been, and will continue to be, invalu- most closely related to human FcγRIIA4. Despite these able to decipher the role of FcγRs in the activity of similarities, there are differences in the intracellular the different antibody isotypes in vivo. Many of the Immunoreceptor tyrosine- based activation motif domains and the cellular expression pattern of these basic principles and mechanisms underlying these (ITAM). A short peptide motif receptors that have to be taken into account when activities have been identified in mice and have been containing tyrosine residues extrapolating data from animal studies to the human recapitulated in humans5. that is found in the cytoplasmic system. Human FcγRIIA, for example, contains an The complexity in the FcγR family is mirrored by tail of several signalling adaptor immunoreceptor tyrosine-based activation motif proteins such as the common (ITAM) the presence of four different IgG subclasses in humans γ- or CD3ζ-chain. It is in its intracellular domain that is not present in mouse (IgG1–IgG4) and mice (IgG1, IgG2a, IgG2b and IgG3), necessary to recruit proteins FcγRIII. In addition to the FcγRI and FcγRII gene which bind with varying affinity and specificity to differ- that are involved in triggering families, there is a unique human receptor, known as ent FcγR receptors6,7. In general, the number of IgG sub- activating signalling proteins. FcγRIIIB, that is only expressed by neutrophils and classes varies widely between different species, ranging The consensus sequence is that is attached to the cell membrane by a glycosyl- from one subclass in rabbits to seven subclasses in horses, Tyr-X-X-(Leu/Ile)-X6–8-Tyr-X-X- (Leu/Ile), where X denotes any phosphatidylinositol (GPI) anchor. The affinity of making it difficult to find orthologues. In humans, for amino acid. the human FcγRs for the different IgG subclasses is example, IgG1 and IgG3 are the most pro-inflammatory NatUre reviews | IMMUNOLOGY volUme 8 | JANUarY 2008 | 35 © 2008 Nature Publishing Group REVIEWS IgG subclasses2,6. In mice, however, IgG2a and IgG2b are B cells functions as an important regulator of the activating the most pro-inflammatory IgG molecules, and these signals that are transmitted by the B-cell receptor (BCR). show a greater activity than mouse IgG1 and IgG3 in Although the lack of inhibitory FcγR expression by NK many in vivo model systems4. cells suggests that these cells might be potent mediators FcγRs are widely expressed throughout the haemat- of antibody-dependent cytotoxicity (ADCC) reactions, a opoietic
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