Mouse and Human Fcr Effector Functions
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Pierre Bruhns Mouse and human FcR effector € Friederike Jonsson functions Authors’ addresses Summary: Mouse and human FcRs have been a major focus of Pierre Bruhns1,2, Friederike J€onsson1,2 attention not only of the scientific community, through the cloning 1Unite des Anticorps en Therapie et Pathologie, and characterization of novel receptors, and of the medical commu- Departement d’Immunologie, Institut Pasteur, Paris, nity, through the identification of polymorphisms and linkage to France. disease but also of the pharmaceutical community, through the iden- 2INSERM, U760, Paris, France. tification of FcRs as targets for therapy or engineering of Fc domains for the generation of enhanced therapeutic antibodies. The Correspondence to: availability of knockout mouse lines for every single mouse FcR, of Pierre Bruhns multiple or cell-specific—‘a la carte’—FcR knockouts and the Unite des Anticorps en Therapie et Pathologie increasing generation of hFcR transgenics enable powerful in vivo Departement d’Immunologie approaches for the study of mouse and human FcR biology. Institut Pasteur This review will present the landscape of the current FcR family, 25 rue du Docteur Roux their effector functions and the in vivo models at hand to study 75015 Paris, France them. These in vivo models were recently instrumental in re-defining Tel.: +33145688629 the properties and effector functions of FcRs that had been over- e-mail: [email protected] looked or discarded from previous analyses. A particular focus will be made on the (mis)concepts on the role of high-affinity Acknowledgements IgG receptors in vivo and on results from antibody engineering We thank our colleagues for advice: Ulrich Blank & Renato to enhance or abrogate antibody effector functions mediated by Monteiro (FacultedeMedecine Site X. Bichat, France), FcRs. Richard Blumberg (Harvard Medical School, USA), Mark Cragg (University of Southampton, UK), Randall Davis Keywords: Fc receptor, FccR, mouse models, antibody-mediated disease, antibody- (University of Alabama at Birmingham, USA), David mediated therapy, high-affinity receptor Dombrowicz (Institut Pasteur de Lille, France), Mark Hogarth (Burnet Institute, Australia), Jeannette Leusen (University Medical Center, Utrecht, The Netherlands), Derry Roopenian (The Jackson Laboratory, USA), Akira Mouse FcRs Shibuya (University of Tsukuba, Japan), Jean-Luc Teillaud (Centre de Recherche des Cordeliers, France) and Marjolein Myeloid cells, B cells, and natural killer (NK) cells in the Van Egmond (VU University Medical Center, The mouse are equipped with a variety of receptors that enable Netherlands). This work was supported by the Institut their interaction with monomeric or aggregated Pasteur, the Institut National de la Sante et de la Recherche – Medicale (INSERM) and by the European Research Council immunoglobulins, antigen antibody immune complexes, (ERC)–Seventh Framework Program (ERC-2013-CoG and/or opsonized (antibody-coated) particles, cells, or sur- 616050). F. J. is an employee of the Centre National de La faces. Most of these receptors bind the Fc portion of Recherche Scientifique (CNRS). All authors state that no conflict of interest exists. immunoglobulins (receptors for the Fc portion of immunoglobulins, FcR) in mice (Fig. 1), whereas other This article is part of a series of reviews receptors bind to glycosylations present on (but not to covering Fc Receptors in Volume 268 of Immunological Reviews. amino acid residues of) the Fc portion of immunoglobulins, e.g. SIGNR1 and DC-SIGN. All these receptors endow mouse myeloid cells, NK cells, and B cells, but not T cells or plate- Immunological Reviews 2015 lets, with the capacity to interact directly with IgM, IgG, IgA, Vol. 268: 25–51 and/or IgE classes of immunoglobulins. Among the 10 FcRs © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons expressed in mice, only half are receptors for a specific class Ltd Immunological Reviews of immunoglobulins, the other half possess a dual specificity 0105-2896 (e.g. binding of IgM and IgA, or IgG and IgE). © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 268/2015 25 Bruhns & Jonsson€ Á FcR effector functions Fig. 1. Mouse Fc receptors (FcRs). Schematic representations of mouse FcRs in respect to the cell membrane (gray bar), in complex with their respective signaling subunits, i.e. b, FcRb subunit; c2, FcRc subunit dimer; b2m, b-2 microglobulin. ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif. TRIM21 is a cytoplasmic molecule. Alleles are identified by the name of À1 the polymorphic/allelic variant. Upper part: Binding affinities for the various immunoglobulin subclasses are given as KA (M ); +, binding but no affinity value has been reported; high-affinity interactions with monomeric Ig are indicated in bold; À, no binding. *: under debate (280, 281). ‘Ag pres.’: antigen presentation. ♮: during infections (211, 282). NB: the affinities of the monomeric (mo) and trimeric (tri) state of FceRII are indicated. Lower part: Expression patterns of FcRs are summarized as follows: +, expression; +/À, expression on a subpopulation; ?, unknown. LSEC, liver sinusoidal endothelial cell. Mouse FcR ligands theless, one should keep in mind that their interaction with Mice express one ‘strict’ IgM receptor (mFclR), two recep- IgE is sufficient to induce biological consequences (2, 3). tors for both IgM and IgA (mPolyIgR and mFca/lR), two All FcRs bind immunoglobulins on the surface of the cells ‘strict’ IgE receptors (mFceRI and mFceRII/mCD23), three expressing them, except mFcRn (4) and mTRIM21 (5) that ‘strict’ IgG receptors (mFccRI, mFcRn, and mTRIM21), and bind immunoglobulins once internalized (TRIM21: three IgG and IgE receptors (mFccRIIB, mFccRIII, and reviewed in 6). The association constants (KA) of these – 9 10 À1 mFccRIV) (1) (Fig. 1). The affinity of the latter dual-specific Ig FcR interactions range over 6 logs, from 3 10 M 9 4 À1 receptors for IgG and IgE is so much in favor of IgG bind- to 2 10 M (Fig. 1). Polymorphisms of mouse FcRs c ing (2 log higher affinity) that most consider and describe have been described for mFc RIIB (Ly17.1 and Ly17.2 c mFccRIIB, mFccRIII, and mFccRIV as IgG receptors. Never- allele) (7, 8) and mFc RIII (V, T, H alleles) (9). In © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 26 Immunological Reviews 268/2015 Bruhns & Jonsson€ Á FcR effector functions addition, mFccRIIB exists as three splice variants that differ the signals mediated by activating FcRs (16, 17). Some in the composition of their intracytoplasmic domain, i.e. mFcRs like mTRIM21 and mFceRII (mCD23) are devoid of mFccRIIB1, mFccRIIB10, and mFccRIIB2 (10). Conse- both ITAM and ITIM but have been reported to induce cell quences on affinity or specificity for immunoglobulin bind- activation or cell inhibition through other mechanisms (5, ing have not been reported for these polymorphic or splice 18–21), respectively. mPolyIgR, mFclR, mFca/lR, mFcRn, variants. Independent of their measured affinity, FcRs are and mTRIM21 are considered as ‘routing/transport’ FcRs as characterized additionally as either ‘low-affinity’ receptors their (apparent) main function consists of internalizing (en- that can only bind immunoglobulins when multimeric (pre- docytosis or phagocytosis), intracellular routing, transcytosis sent in an immune complex, aggregated, or opsonized) and (by polarized cells), or recycling of immunoglobulins. Nota- ‘high-affinity’ receptors that can also bind free/monomeric bly, internalization of immunoglobulins is a common role immunoglobulin. Receptors for pentameric IgM and/or for all mFcRs; the only exceptions being mFcRn and dimeric IgA (i.e. polyIgR, FcaR, Fca/lR) escape this classifi- mTRIM21 that bind immunoglobulins once already pinocy- cation. High-affinity FcRs in mice are thus mFceRI for IgE, tosed or endocytosed by other receptors, and the mFccRIIB1 mFccRI for IgG2a (but not IgG2b or IgG3), mFccRIV for variant that induces capping of immune complexes on the IgG2a and IgG2b (but not for IgE), and mFcRn for all IgG cell surface (10, 14). Internalization and routing of antibod- subclasses. Due to the high circulating levels of IgG in ies by FcRs represents an essential mechanism for antigen mouse serum (6 mg/mL), it is expected that the binding processing/presentation by the immune system, as anti- sites of high-affinity IgG receptors are constitutively satu- body-bound antigen is not dissociated from antibodies dur- rated by IgG in vivo, at least on circulating cells: the concept, ing these processes. It follows indeed that processing and beliefs, and in vivo evidence of biological functions associated presentation of antibody-bound antigen is considerably to these high-affinity FcRs are discussed in section ‘The more efficient by antigen-presenting cells than that of free (mis)concepts on high-affinity IgG receptors: FccRI and antigen (22–27). Remarkably, the repertoire of antigenic FccRIV’ in this review. epitopes presented following antigen–antibody internaliza- tion differ depending on the type of mFcR mediating the internalization: when mFccRIIB is involved a restricted set Mouse FcR functions of T-cell epitopes is presented compared to when mFccRIII All mouse FcRs can induce diverse biological functions fol- is involved after immune complex internalization, probably lowing binding of their ligand, mostly when the ligand is due to cell activation concomitantly triggered by the latter in a multimeric state (in an immune complex,