Signal transduction by immunoglobulin Fc receptors

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1 Signal transduction by immunoglobulin Fc receptors Gabriela Sánchez-Mejorada and Carlos Rosales Immunology Department, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City Abstract: Receptors for the Fc portion of immunoglobulin molecules (FcR) present on leukocyte cell membranes mediate a large number of cellular responses that are very important in host defense. Cross-linking of FcR by immune complexes leads to functions such as phagocytosis, cell cytotoxicity, production and secretion of inflammatory mediators, and modulation of the immune response. Molecular characterization of FcRs indicates the existence of several types of these receptors, which seem to be redundant in their cell distribution and function. There is a great deal of interest in understanding how these various receptors signal the cell to respond in different ways during inflammation and the immune response. Previous studies indicate that FcR signaling shares elements with the T and B cell antigen receptors. Signaling is initiated in all of them by activation of tyrosine kinases of the Src and ZAP-70 families. Subsequent events, which vary depending on the cell type and receptor involved, include activation of other enzymes such as phospholipase C 1, phosphatidylinositol-3- kinase, and mitogen-activated protein kinase. Several recent lines of research, including studies of phagocytosis by FcR-transfected cells, antibodydependent cytotoxicity by natural killer cells, mast cell degranulation, and FcR-deficient mice, have given us new insights on the signal transduction pathways activated by FcRs. This review describes the advances in these areas and presents a general model for FcR-mediated signaling. J. Leukoc. Biol. 63: ; Key Words: phagocytosis tyrosine phosphorylation inflammation IgG. Fc R-mediated responses include the following: phagocytosis, antibody-dependent cell-mediated cytotoxicity (ADCC), release of arachidonate metabolites, histamine, and other inflammatory mediators, production and secretion of lymphokines, and modulation of cell proliferation and differentiation (Table 1). Fc Rs are different from other types of receptors (like those for hormones, for example) in that cross-linking of the receptors on the plane of the cell membrane by polyvalent immune complexes (such as opsonized cells or bacteria), rather than just IgG binding, is the triggering event. Cross-linking the receptors with special reagents such as anti-fc R antibodies results in effective cell activation [3, 4]. Molecular characterization of the primary structure of these receptors has been the first line of research in trying to understand how Fc Rs contribute to immune cell regulation. Great progress was made through the cloning of cdnas and genes that code for this family of receptors. A nearly complete description of the structure and cell expression of Fc Rs has been achieved today [5]. The next step (and current research) is to try to understand what are the particular functions and signals mediated by each one of these diverse Fc Rs. After activation of Fc Rs, by cross-linking them with immune complexes or IgG-opsonized particles, several tyrosine residues in the cytoplasmic tails of these receptors become phosphorylated [6]. These tyrosines are located within a common motif identified in many chains of antigen and Ig Fc receptors [7, 8]. This motif, known as ITAM for immunoreceptor tyrosine-based activation motif [9, 10], consists of two pairs of tyrosines and leucines within the consensus sequence D/E-X 7 - D/E-X 2 -Y-X-X-L-X 7 -Y-X-X-L, and it has been shown to be important for signal transduction. It is interesting to note that the motif is also found in certain viral proteins, including bovine leukemia virus gp30 and Epstein-Barr virus (EBV) proteins LMP2A and EBNA2, suggesting the possibility that INTRODUCTION Membrane receptors for the Fc portion of immunoglobulin (antibody) molecules are expressed on many hematopoietic cell types. Fc receptors for IgG (Fc R), IgE (Fc R), and IgA (Fc R) are all members of the immunoglobulin gene superfamily [1, 2]. Cross-linking of these receptors on the leukocyte cell membrane activates a plethora of cellular responses that play important roles in inflammation and immunity. In this way, receptors for antibodies form a molecular link between the humoral and cellular branches of the immune system. The most abundant and better studied of these receptors are those for Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; BCR, B cell receptor; EBV, Epstein-Barr virus; Fc R, receptor for the Fc portion of IgG; GPI, glycosylphosphatidylinositol; IgG, immunoglobulin G; IP 3, inositol 1,4,5-trisphosphate; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; MAPK, mitogenactivated protein kinase; NK cell, natural killer cell; PI3-kinase, phosphatidylinositol-3-kinase; PKC, protein kinase C; PLC, phospholipase C; S1P, sphingosine-1-phosphate; TCR, T cell receptor; KARs, killer cell activation receptors; KIRs, killer cell inhibitory receptors. Correspondence: Dr. Carlos Rosales, Department of Immunology, Instituto de Investigaciones Biomédicas, UNAM, Apto. Postal 70228, Cd. Universitaria, México D.F , Mexico. carosal@servidor.unam.mx Received September 9, 1997; revised January 21, 1998; accepted January 22, Journal of Leukocyte Biology Volume 63, May

2 Cell type Neutrophil TABLE 1. Macrophage Mast cell NK cell Fc Receptor-Mediated Functions of Immune Effector Cells Function Phagocytosis Respiratory burst Granule secretion Phagocytosis ADCC Inflammation mediators release Degranulation Cytokine production ADCC Cross-linking of FcR on the membrane of leukocytes by immune complexes or IgG-opsonized particles activates several cellular effector functions. Phagocytosis is the engulfment and destruction of antibody-coated targets. Antibodydependent cell-mediated cytotoxicity (ADCC) is a major function of NK cells, but it can also be performed by macrophages and neutrophils. Inflammation mediators such as leukotrienes, prostanglandins, histamine, cytokines, and reactive oxygen products are released by various cells. these proteins may have a signaling function during viral infections [9]. In the actual accepted model for immunoreceptor signaling, phosphorylated tyrosines in the ITAM become docking sites for protein tyrosine kinases of the Syk and ZAP-70 families, which are then activated at this site [11]. These activated kinases catalyze the phosphorylation and activation of several substrates, including phospholipase C (PLC) 1; phosphatidylinositol-3-kinase (PI3-kinase), a lipid kinase consisting of a p85 regulatory subunit and a p110 catalytic subunit; mitogenactivated protein kinase (MAPK), etc. The particular substrate involved depends on the cell type, cellular function activated, and particular type of receptor engaged. We will see that, within a general model for FcR-mediated signal transduction, there is variability for the particular functions and signals of each FcR. from its three genes and also alternative splicing of Fc RIIB [12], have different distribution in hematopoietic cells. Fc RIIA is found mainly in phagocytic cells (neutrophils, monocytes, and macrophages), whereas Fc RIIB is expressed in B and T lymphocytes [13]. Fc RIII (CD16) also has two Ig-like domains. Its -chain shows a molecular mass in electrophoresis gels varying from 50 to 70 kda. Fc RIIIA is a receptor with a transmembrane portion and an intracytoplasmic tail. It is expressed mainly on natural killer (NK) cells and macrophages [14]. Fc RIIIB (CD16) is present exclusively on neutrophils and it is a glycosylphosphatidylinositol (GPI)-linked receptor lacking transmembrane and cytoplasmic domains [14]. No other subunits are known to associate with it, but it may signal in cooperation with other receptors [13] (Fig. 1). Fc Rs are members of the Ig gene superfamily and share a highly homologous extracellular portion that contains the IgG binding domain. Most of their differences are concentrated in the transmembrane or cytoplasmic regions, suggesting that they are related to signal transduction mechanisms activated by each type of receptor [5, 15]. Having several Fc R cdnas cloned, it was realized that other polypeptide chains are needed for some Fc R expression and function. Fc RI and Fc RIII exist as multimeric complexes. In each case, the -chain that contains the IgG binding domain associates with dimers of homologous disulfide-linked gamma and zeta chains. These subunits were originally identified as part of the Fc RI and the T cell receptor (TCR), respectively [16] (Fig. 1). It was indicated above that an almost complete understanding of the molecular structure of Fc R and their genes has been achieved. However, the biological significance and functional role played by each receptor is still poorly characterized. Even though several receptors show similar binding specificities for IgG subclasses and seem to mediate the same cellular responses, it is still largely unknown whether a particular isoform Fc RECEPTORS Several lines of evidence, including molecular size, pattern of cell expression, recognition by several monoclonal antibodies (mab), and gene structure coding for them, have found receptors for the Fc portion of IgG to exist in three classes: Fc RI, Fc RII, and Fc RIII [3, 5, 12]. Each class includes several individual receptor forms. Fc RI binds monomeric IgG and is classified as a high-affinity receptor. Fc R types II and III present only avidity for multimeric immune complexes and are therefore named low-affinity receptors. Several genes encode Fc Rs in each class. Three genes, known as A, B, and C, exist for both Fc RI and Fc RII. Two genes, A and B, code for Fc RIII [5]. They are all located in chromosome 1 at q Fc RI (CD64; a 72-kDa sialoglycoprotein) has three Ig-like domains in its extracellular portion. This feature is thought to be responsible for its high IgG binding affinity. It is expressed on monocytes, macrophages, and interferon- -stimulated neutrophils. Fc RII (CD32; a 40-kDa sialoglycoprotein) has only two Ig-like domains in the extracellular portion, which makes it a low-affinity receptor for IgG. Its several isoforms, derived Fig. 1. Fc receptor structure. Schematic representation of FcRs indicating their polypeptide chains (Greek letters) and their genes (Latin letters). As members of the immunoglobulin superfamily their ligand binding chains ( ) present two or three Ig-like domains (circles). All of them have a transmembrane domain and a cytoplasmic tail with the exception of Fc RIIIB, which is GPI-linked to the membrane. Some receptors have associated or subunits that are important in receptor expression and signaling. Fc RIIA and Fc RIIB have functional domains involved in signal transduction. The rectangle in the cytoplasmic tail of some chains represents the immunoreceptor tyrosine activation motif (ITAM) found in several receptors important in immune responses [9, 10]. The cylinder in Fc RIIB represents the domain (ITIM) involved in down-regulating B cell receptor signaling. In addition to the subunits, Fc RI has a unique subunit. 522 Journal of Leukocyte Biology Volume 63, May 1998

3 of Fc R mediates a unique effector function. Indeed, a redundancy for cellular activation via Fc R seems to be the case, as demonstrated, for example, by the capacity of each type of Fc R to mediate phagocytosis [17]. Thus, the differences in the cytoplasmic tails of these receptors may indicate that in different cell types particular Fc R use distinct signal transduction pathways. One of the first biochemical changes identified for Fc R signaling was a rise in cytosolic Ca 2 concentration. However, this change had to be a later event because other second messengers, such as inositol trisphosphate, are needed for calcium release from intracellular stores. It is now clear that the initial signal from these receptors and others, such as Fc RI, TCR, and BCR is the activation of tyrosine kinases. Phosphorylation of tyrosine residues within their ITAMs is the hallmark of activation for all these immune receptors [8, 10]. Src gene family kinases, including Src, Fyn, Fgr, Hck, and Lyn have been identified in phagocytic cells. These kinases are associated with the inactive Fc Rs. Upon cross-linking of the receptors the kinases become active and phosphorylate the receptor cytoplasmic tails. These phosphotyrosine residues serve as binding sites for other kinases such as Syk, via its SH2 domains [11, 18]. Substrates for these activated kinases are now beginning to be identified. Some of them are PLC 1 and PLC 2, which are responsible, when tyrosine phosphorylated, of phosphatidylinositol phosphate hydrolysis and intracellular calcium release [19 23]. A 115-kDa phosphorylated protein that associates with PI3-kinase, probably through the SH2 domain of the p85 regulatory subunit of the enzyme, is also phosphorylated. PI3-kinase is activated after Fc R crosslinking [24, 25] and it seems to be important for phagocytosis [17, 24] (see below). Some proteins of the Ras signaling pathway, such as Ras and MAPK, have also been found phosphorylated upon Fc R ligation [26 29]. Paxillin, a cytoskeleton-associated protein that is found with F-actin beneath nascent phagosomes, is also tyrosine phosphorylated after Fc R activation [30]. PHAGOCYTOSIS Phagocytosis is the process of recognition and engulfment of microorganisms or tissue debris that accumulate at sites of infection and inflammation. This function, essential for successful host defense, is performed most efficiently by migrating leukocytes denominated professional phagocytes. These include neutrophils, monocytes, and macrophages. Phagocytosis starts when an invading microorganism is detected by specific receptors on the cell membrane. The three classes of Fc receptors, Fc RI, Fc RII, and Fc RIII are found on the surface of professional phagocytes. These receptors allow phagocytes to recognize and ingest IgG-coated microorganisms and other particles [31]. The various isoforms of Fc Rs present highly conserved extracellular portions (Fig. 1), but their cytoplasmic tails are heterogeneous. This fact suggested that all Fc Rs may not be involved in phagocytosis. One of the major obstacles for understanding the Fc R requirements for phagocytosis has been the fact that multiple isoforms are expressed on each type of phagocytic cell. So it has been difficult to determine which Fc Rs are responsible for this function in the absence of other Fc Rs. The same is true for several other Fc R-induced cellular responses. One experimental system that has been very helpful for dissecting the molecular signals involved in phagocytosis consists in expressing a single Fc R in a cell that does not have endogenous Fc Rs. Fibroblasts [32, 33], mast cells [34], and COS-1 cells (a monkey kidney fibroblast/epithelial cell line) [35] have all been shown to support phagocytosis of IgG-coated particles when transfected with cdna from certain Fc Rs. It was observed that not all cell types were capable of this function even when expressing Fc Rs, in part because a successful phagocytic signal leads to rearrangement of the actin cytoskeleton [31]. This implies that a phagocytic Fc R needs to activate a signaling pathway that involves biochemical and also cytoskeletal changes. Only cells that contain a functional phagocytic machinery will allow Fc Rs to activate this function. COS-1 cells seem to have sufficient phagocytic machinery to allow Fc R-mediated phagocytosis by all types of Fc Rs [17]. With this system it was possible to establish that a particular Fc R in the absence of other Fc R is capable of phagocytosis of IgG-coated erythrocytes but with particular requirements for each of them [17]. In COS-1 cells the low-affinity Fc RIIA easily mediated phagocytosis, whereas its isoforms Fc RIIB1 and Fc RIIB2 did not [36]. Also, the high-affinity Fc RI alone was not functional [37] and Fc RIIIA required the presence of its subunit both for expression and function [38, 39]. These data permitted a closer look at the structural differences in the various cytoplasmic tails of Fc R to identify what elements are important for signaling. Fc RIIA contains two copies of the conserved sequence Y-X-X-L found in the consensus ITAM of immune receptors [7 10]. Fc RIIB1 and Fc RIIB2 present only a single Y-X-X-L sequence in their cytoplasmic tails. This observation and also the fact that Fc RIIA mutants lacking the cytoplasmic tail can bind IgG-opsonized erythrocytes but are not phagocytic [35, 40], suggested that these sequences are important for a phagocytic signal. The sequence Y-M-L-T from Fc RIIA was then introduced upstream of the existing Y-S-L-L sequence in Fc RIIB2, creating a new mutant receptor that had a cytoplasmic tail with a similar ITAM as the one in Fc RIIA [36]. This receptor allowed IgG-mediated phagocytosis, although with lower activity than that of wild-type Fc RIIA [36]. This data showed that the number and location of Y-X-X-L sequences in the cytoplasmic tail are important for making a particular Fc R competent for phagocytosis. Underlying the importance of these tyrosine residues for a phagocytic signal is the observation that tyrosine kinase inhibitors blocked phagocytosis by Fc RIIA in COS-1 cells. Substitution of either one of these tyrosines for phenylalanine resulted in reduced tyrosine phosphorylation of the receptor and also in reduced phagocytosis. Changing both residues for phenylalanine completely blocked phagocytic function [40]. Fc RI did not render COS-1 cells phagocytic even though they bound IgG-coated erythrocytes efficiently. However, this receptor was able to activate phagocytosis in other cell types, such as macrophages that express several Fc Rs [41]. This Sánchez-Mejorada and Rosales Fc receptor signal transduction 523

4 suggested that macrophages contain elements not present in COS-1 cells that are important for Fc RI-mediated phagocytosis. To confirm this idea, the murine macrophage cell line P388D1 was transfected with Fc RI. The receptor was then functional in these transfectants [42]. The best candidate for the macrophage element required for phagocytosis was the -chain that associates with Fc RIIIA. Coexpression of the -chain with Fc RI rendered COS-1 cells phagocytic. Moreover, a mutant Fc RI lacking its cytoplasmic domain was also functional in the presence of the -subunit [42]. Even though the cytoplasmic tail of Fc RI does not exhibit an ITAM, tyrosine kinase inhibitors also blocked Fc RI-mediated phagocytosis [42]. These data clearly indicated that the cytoplasmic tail of Fc RI is not required for phagocytosis, but still tyrosine phosphorylation of ITAMs on the -chain is an important initial element for phagocytic signaling [10]. However, earlier reports showed that Fc RI was able to activate Ca 2 signaling in COS-1 cells in the absence of the -subunit [43]. Therefore, the cytoplasmic tail of Fc RI seems to be important to activate some cellular functions but not others. The case of Fc RIII is attractive because its two isoforms are very different. Fc RIIIA is a multimer complex formed by the IgG-binding -chain and a disulfide-linked homodimer or heterodimer of -and -chains [5, 44], whereas Fc RIIIB is a GPI-linked receptor that lacks membrane and cytoplasmic regions [45, 46]. When Fc RIIIA was transfected into COS-1, it was capable of sending a phagocytic signal in the absence of other Fc Rs, but the presence of the -chain was required both for membrane expression and function [38, 39]. Coexpression of the -chain also resulted in a functional Fc RIIIA, but it showed a much lower efficiency for phagocytosis [38]. This observation is interesting because phagocytes express the -chain and lymphocytes the -chain. Exchanging domains of the cytoplasmic regions of the - and -chains, it was found that the functional differences between these subunits are mainly determined by the two internal X-X amino acids in the pair of conserved sequences Y-X-X-L within their ITAM [47]. Supporting the involvement of the -chain tyrosines in Fc RIIIA phagocytic signal is the fact that tyrosine kinase inhibitors markedly inhibited phosphorylation of the -subunit as well as phagocytosis [39]. Despite the absence of transmembrane and cytoplasmic regions, Fc RIIIB is capable of initiating signal transduction events such as calcium release [48, 49] and actin polymerization [50]. The way Fc RIIIB transduces a signal is not clear, but based on results found with other Fc Rs it is thought that this receptor associates with other molecules on the cell membrane to initiate phagocytosis. Fc RIIA has been suggested to be one of these molecules [48, 51]. However, fibroblasts transfected with Fc RIIIA are capable of IgGmediated phagocytosis in the absence of other Fc Rs, when at the same time the complement receptor type 3 (CR3, Mac-1) is expressed [33]. Other reports have indicated that there is a functional relationship between Fc RIIIB and Mac-1 in neutrophils [52 55]. Moreover, it has also been shown that these two receptors are closely associated on the cell membrane and that their union is mediated by lectin-like interactions [56, 57]. The mechanisms by which Fc RIIIB may recruit the signaling capabilities of Fc RIIA, Mac-1, or both, remain unknown. In coming years this will be an active area of research in the field of Fc R signal transduction. Data described above have clearly indicated that representative elements from each Fc R class are capable of IgGmediated phagocytosis and, although they have particular requirements, in all cases (except Fc RIIIB) phosphorylation of ITAM sequences in the cytoplasmic tail of their -chain or associated -subunits is a constant requirement. Two classes of protein tyrosine kinases, Src and Syk families, have been found to play a role in Fc R signaling. Inactive receptors are associated with kinases of the Src gene family kinases. In phagocytes the kinases Src, Fyn, Fgr, Hck, and Lyn have all been identified [6, 58]. These kinases have a common structure: the amino-terminal domain is myristoylated and serves to anchor the kinase to the cell membrane, it is followed by SH3 and SH2 domains, then a catalytic domain, and a short carboxyl-terminal tail. Within this tail there is a tyrosine residue (Y527 in Src) that when phosphorylated inhibits the catalytic activity of these enzymes [59, 60]. Due to its lipid anchor these kinases are in close proximity to the cytoplasmic tails of Fc R, but remain inactive (Fig. 2). It is thought that an intramolecular interaction between the phosphotyrosine in its tail and its own SH2 domain maintains the Fig. 2. Fc receptor activation in phagocytosis. Schematic representation of the early events of Fc R stimulation during phagocytosis. This figure represents the most probably occurrence, but the actual sequence of events has not been established. (A) Inactive receptors are in close proximity of inactive Src gene family kinases. Src is inactivated by an intramolecular bridge between its phosphotyrosine 527 and its SH2 domain. (B) On Fc R cross-linking by an IgG-coated particle, Src kinases become activated and bind via their SH2 domain to phosphotyrosine residues in the cytoplasmic tail of the Fc R. These phosphotyrosine residues are also anchor sites for Syk kinase, which is in turn activated. Several possible targets for this kinases are shown. 524 Journal of Leukocyte Biology Volume 63, May 1998

5 enzyme inactive [59]. During Fc R cross-linking the associated kinases become active. Activation is achieved by dephosphorylation, possibly through the cell surface leukocyte-specific phosphatase CD45 [61, 62], of the carboxyl-terminal tyrosine and liberation of the catalytic domain. Also, phosphorylation of another tyrosine residue within the catalytic domain (Y416) activates the kinase [59]. Once the kinase SH2 domain is free, it can bind to the phosphotyrosine residues in the ITAM of the activated Fc Rs (Fig. 2). So we see that Src gene family kinases are involved in the very early steps of phagocytosis signal transduction but the exact mechanism by which Fc R crosslinking induces tyrosine kinase activation remains poorly understood [6, 63, 64]. Another kinase, Syk (72 kda), has been implicated in Fc R signaling. Syk belongs to the ZAP-70 kinase family. These enzymes are not myristoylated and therefore are exclusively cytoplasmic. Syk is present in all hematopoietic cells, whereas ZAP-70 is expressed in T cells and NK cells [65 67]. Syk was found to coimmunoprecipitate with the -chain of Fc RI and Fc RIIIA in macrophages and Fc RI in mast cells [68, 69]. On cross-linking of Fc RI in monocytes or Fc RIIIA in macrophages, Syk is phosphorylated and its enzymatic activity augmented [30, 66, 68 70]. Fc R-transfected COS-1 cells, although phagocytic, presented lower activity levels than macrophages [35, 36, 38, 39], suggesting that there was another element present in leukocytes that was important for phagocytosis. Because Syk is exclusively present in leukocytes, it was a good candidate for this component. COS-1 cells cotransfected with Syk, the -subunit, and Fc RI or Fc RIIIA, showed a higher phagocytic activity than the one of Fc RI/ or Fc RIIIA/ transfectants [71]. Furthermore, the two cytoplasmic Y-X-X-L sequences in the ITAM of the -chain were required for this Syk effect [47, 71], suggesting that Syk binds to, via its SH2 domains, and is activated by phosphotyrosine residues in the ITAM (Fig. 2). This interaction seems specific because the kinase ZAP-70 was not able to stimulate Fc RIIIAmediated phagocytosis [47]. The essential role for Syk in phagocytosis signal transduction is emphasized by the demonstration that Syk is a necessary component in ITAM-dependent activation of actin assembly [72], and also because chimeric transmembrane proteins bearing Syk cytoplasmic domains, but not Src family kinase domains, trigger autonomously phagocytosis and actin redistribution in COS-1 cells [73]. More recently, Syk anti-sense oligonucleotides, which inhibit Syk production by blocking its mrna, were shown to prevent Fc RIIAmediated phagocytosis in monocytes [74]. Downstream events of Syk activation are at this moment not clearly defined. However, a series of phosphorylated proteins have been detected after Fc R stimulation. Some of them are the Fc RII -chain and the -subunits of Fc RI and Fc RIIIA [30, 63, 66, 68, 75, 76]. The enzymes PLC 1 and PLC 2 [19 23], which are responsible for induction of the second messengers inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG) and the enzyme PI3-kinase, whose role in phagocytosis was confirmed by the inhibitory effects of wortmannin, a fungal product that specifically inhibits PI3-kinase by binding irreversibly to its p110 catalytic subunit [17, 24]. The protooncogene p95 Vav, p62/gap-associated protein, and p21ras/ GAP [68, 77] have also been detected. Discovering the role played by each of these proteins in Fc R signal transduction will be the focus of future research. Among all Fc R downstream second messengers, a rise in cytosolic calcium concentration was always considered relevant for phagocytosis because all Fc Rs seem to induce it [48, 49, 78] and because this Ca 2 concentration increase is greatest in the cytoplasm surrounding the new phagosome [79]. However, different roles for these calcium transients during Fc Rmediated phagocytosis have been suggested based on earlier reports that IgG-mediated phagocytosis by human neutrophils was Ca 2 -dependent [80], whereas that by macrophages was Ca 2 -independent [81, 82]. It was later shown that this Ca 2 -dependence occurs in the same cell type depending on the activation state of the cell [83]. These data suggested that the phagocytosis signaling may vary in response to signals from other receptors on the phagocyte. To further explore the Ca 2 role in phagocytosis, the murine macrophage P388D1 cell line was transfected with several mutants of Fc RIIA and the Ca 2 -dependence of its phagocytic activity compared with that of normal neutrophils and monocytes. Results suggested that Ca 2 -independent phagocytosis is a property associated with the utilization of -chains by Fc R [84]. Another unresolved issue is the actual second messenger that causes the Ca 2 increase. IP 3 is the principal second messenger responsible for calcium release from intracellular stores [85, 86]. However, in neutrophils [49] and mast cells [87], the Ca 2 release after Fc R activation has been found to be independent of this metabolite. Also, indirect evidence suggested that L-plastin, an actin-binding protein that is phosphorylated in response to phagocytosis [88, 89], may participate in the IP 3 -independent Ca 2 rise mediated by Fc RII in neutrophils [90]. Recently, it was proposed that sphingosine-1-phosphate produced after Fc RI cross-linking is the second messenger responsible for the cytoplasmic Ca 2 rise [87]. Despite PLC activation, IP 3 may not be the relevant second messenger for Ca 2 release employed by Fc Rs. ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY (ADCC) NK cells are a subpopulation of lymphocytes with a distinct phenotype (CD16, CD3, surface Ig ) that can mediate lysis of certain tumor cells and virus-infected cells and that can secrete certain cytokines such as interferon-, tumor necrosis factor, and granulocyte-macrophage colony-stimulating factor [91 93]. NK cells play an essential role in host defense because they are involved in generating resistance against infectious microorganisms, controlling tumor growth, and modulating the immune response. These various cellular responses are activated through specific receptors on the NK cell membrane that bind soluble or cell-associated ligands. Due to their importance in host defense, and because NK cells express only one Fc R, Fc RIIIA, on their surface, these cells have become an interesting system for studying Fc Rmediated signal transduction mechanisms. NK cells can kill susceptible cells without prior sensitization and in the absence of antibody through a function called natural killing. They can Sánchez-Mejorada and Rosales Fc receptor signal transduction 525

6 also recognize and destroy immunoglobulin-covered cell targets through their Fc R. This ADCC is the main Fc R function of NK cells. ADCC is initiated by ligation of Fc RIIIA to antibodies bound to cell-associated antigens. As mentioned earlier, Fc RIIIA cells exist as a multimer complex formed by the -chain and homodimers or heterodimers of - and -chains [94 96] and ITAM sequences in these chains are critical for generation of Fc R-mediated signaling [9, 10]. In NK cells the -chains seem to be more relevant for ADCC, since -/- mice, but not -/- mice, are not capable of mediating this function [97, 98]. This has emphasized the concept that a particular ITAM is responsible for only certain responses. Supporting this idea is the observation that different ITAMs bind to different signaling molecules, such as PLC 1, PI3-K, Syk, and ZAP-70 [25, 67, ]. During ADCC, increased tyrosine kinase activity is one of the earliest events detected after Fc RIIIA cross-linking, and tyrosine kinase inhibitors have been shown to prevent this function [102]. Lck, a Src gene family kinase, is detected in immunoprecipitations of Fc RIIIA from NK cells and its catalytic activity is enhanced in vitro after Fc R activation [103, 104]. Similarly, ZAP-70 and Syk kinases are tyrosine phosphorylated in NK cells after Fc R ligation [105, 106]. These findings would suggest that in NK cells Fc RIIIA follows a similar signaling pathway to the one described for Fc Rmediated phagocytosis. However, Lck and the phosphatase CD45 are not needed for NK cell ADCC [107]. Similarly, ZAP-70 was found not to be required for NK cell cytotoxicity [108, 109]. Other Src gene family kinases that could take the place of Lck have not been found associated to Fc RIIIA. Instead, it seems that Syk may have the potential of directly phosphorylating ITAMs and to signaling in a Src familyindependent manner [110]. Supporting this is the fact that CD45, an important regulator of Src family kinases, is not required for signaling initiated by immunoreceptors that are coupled to Syk [111, 112]. Therefore, in NK cells, Fc R cross-linking mediates Syk activation and promotes its binding to the -chain ITAM to initiate ADCC, all in the absence of Lck, CD45, or ZAP-70 (Fig. 3). Several other downstream signaling molecules that are important for ADCC and cytokine secretion have been identified in NK cells after Fc R activation (Fig. 3). Both PLC 1 and PLC 2 are phosphorylated after Fc RIIIA cross-linking [19, 20]. Activated PLCs are responsible for inositol trisphosphate and diacylglycerol formation. These second messengers lead to calcium release and protein kinase C (PKC) activation, respectively. An increase in cytoplasmic Ca 2 concentration is necessary for the granule release involved in the delivery of the lethal hit [93, 113]. PI3-kinase is also activated after Fc R ligation [25] and it seems to be very important for ADCC because wortmannin inhibits this function [114]. Elements that participate in receptor-tyrosine-kinase signaling pathway, such as Ras, in association with Shc and Grb2 [77], and MAPK [115] are also activated by Fc R cross-linking. Phospholipase A 2, which is responsible for arachidonic acid release, was activated in a MAPK-dependent manner [115] (Fig. 3). The roles played by these second messengers are still poorly defined but they will be sorted out in future research. Fig. 3. Fc receptor activation in ADCC by NK cells. Schematic representation of the early events of Fc RIIIA signaling in NK cells. (A) Although Lck is associated with the inactive Fc R, it does not participate in ADCC activation. (B) On Fc R aggregation, Syk seems to phosphorylate the -chain ITAM and then bind to it via its SH2 domains. The activated kinase leads to phosphorylation of PLC, which produces IP 3 and DAG. In turn, IP 3 causes a rise in cytosolic calcium concentration that is important for the granule release involved in cytotoxicity. DAG is an activator of PKC. PI3-K phosphorylation is required for ADCC. Elements of the Ras signaling pathway, such as MAPK are also activated. Oncoprotein Shc and adaptor protein Grb2 are involved in Ras activation. Natural killing, initiated by killer cell activation receptors (KARs) and Fc R-dependent ADCC are very similar NK cell functions but important differences in their signaling pathways have been observed. For example, natural killing of K562 cells, which are a typical NK cell target, is PKC-dependent and PI3-K-independent, whereas Fc R-mediated ADCC is controlled by a PKC-independent and PI3-K-dependent pathway [114]. NK cells have also been instrumental in understanding how activation signals are regulated. Special receptors, denominated killer cell inhibitory receptors (KIRs), recognize MHC class I molecules on target cells and can prevent NK cell cytotoxicity. This could be considered to be a safe mechanism to prevent accidental killing of self cells. KIRs are structurally different but they all seem to employ a common inhibitory mechanism [116, 117]. Tyrosine residues in their cytoplasmic tail are phosphorylated and then become binding sites for other molecules with inhibitory activity (Fig. 4). The first clues for this inhibitory mechanism came from a particular Fc R, Fc RIIB. Cross-linking Fc RIIB on B cells prevents proliferation and differentiation of these lymphocytes. A 13-amino-acid sequence, present in the cytoplasmic tail of Fc RIIB, was found to be necessary and sufficient for inhibitory activity. This 526 Journal of Leukocyte Biology Volume 63, May 1998

7 Fig. 4. Fc receptor and KIR inhibition mechanism. Fc RIIB on B cells and KIRs on NK cells present a similar mechanism of action. In this model, (A) when Fc RIIIA is aggregated on the NK cell membrane by an IgG-coated cell its -chains become phosphorylated and Syk binds to them, delivering a positive signal downstream. (B) In contrast, if the KIR is also engaged by class I MHC molecules, it gets tyrosine phosphorylated and recruits the phosphatase SHP-1, which eliminates phosphate groups from tyrosine residues on the -chain ITAMs. The unphosphorylated Fc RIIIA cannot initiate signaling. This is a speculative model because there is still controversy concerning the sequence of events. sequence defined an inhibitory domain that is known as immunoreceptor tyrosine-based inhibitory motif (ITIM) [ ]. Once the ITIM is tyrosine phosphorylated by Src family kinases [121], it recruits phosphatases that block tyrosine phosphorylation-mediated signaling (Fig. 4). This is a reasonable model to explain the function of these inhibitory receptors. However, there is still controversy concerning this sequence of events. Fc RIIB and KIR ITIMs bind the tyrosine phosphatase SHP-1 [ ]. SHP-1 binding is clearly important for IgG-mediated killing, since overexpression of a catalytic inactive form of SHP-1 (acting as a dominant negative) reverts the inhibitory action of KIR ligation on ADCC [121, 125]. Another SH2 domain-containing inositol phosphatase, SHIP, binds to the Fc RIIB ITIM [123, 126], but does not seem to bind to KIRs [116]. These data suggest that KIR and Fc RIIB utilize SHP-1 and SHIP phosphatases to inhibit at different levels. SHP-1 blocks tyrosine phosphorylation-mediated signaling, whereas SHIP prevents increases of soluble inositol phosphates and cytoplasmic calcium [116]. Recently, it has also been suggested that Fc RIIB inhibitory activity in B cells is in part due to an ineffective activation of Ras [127]. MAST CELL DEGRANULATION MEDIATED BY Fc RI Mast cells and basophils release several inflammatory mediators, including histamine (stored in granules), arachidonic acid metabolites, and cytokines. Histamine and other substances contained in the secretory granules are particularly important in eliciting the symptoms associated with allergic reactions. Activation for mast cell degranulation is mediated by a particular class of immunoglobulin, IgE. IgE molecules bind and remain ligated to a special Fc receptor, the high-affinity Fc RI (Fig. 1), on the membrane of these cells. Cross-linking of this receptor by a multivalent antigen is the trigger for mast cell degranulation. Because Fc RI is the only FcR on these cells, it has also been a very helpful model for studying FcR signaling. Fc RI is a multimeric receptor with -, -, and a homodimer of - subunits [128]. Both - and -chains present an ITAM in their cytoplasmic tails [7, 9, 10], which serve as binding sites for tyrosine kinases. On receptor cross-linking a series of proteins are tyrosine phosphorylated [129, 130], including PLC [131]. Also, rises in Ca 2 concentration [87, 132] and diglycerides are observed, which lead to activation of protein kinase C [133, 134]. Tyrosine phosphorylation and increased activity of MAPK are also detected [27, 28, 135]. Similar to other immunoreceptors, a Src family kinase is associated with the inactivated receptor. In unstimulated RBL-2H3 cells (rat mast cell line) the kinase Lyn is found with the -chain of Fc RI [69, 136]. Activation of the receptor causes tyrosine phosphorylation of both the - and -subunits [69, 137] and recruitment of the kinase Syk to the receptor complex [69]. This sequence of events is supported by the finding that N-acetyl-L-cysteine inhibits Fc RI-mediated Syk Sánchez-Mejorada and Rosales Fc receptor signal transduction 527

8 activation but not Lyn activation and phosphorylation of - and -chains [138]. Using protein chimeras formed by the extracellular portion of the IL-2 receptor and the cytoplasmic tail of the -chain, it was found that the -chains are sufficient for many Fc RI functions, including degranulation and Ca 2 mobilization [69]. The -chain acts as an amplifier for signaling, providing a five- to sevenfold increase in Syk activation and calcium mobilization over the -chain signal [139]. Although the leukocyte-specific phosphatase CD45 is required for the regulation of Src family kinase activity and tyrosine phosphorylation of - and -chains after Fc RI clustering [62], activation of Syk is dependent on the phosphorylation of the -chain and independent of hematopoietic specific phosphatases [116]. Studies with the RBL-2H3 cell line suggest that more than one signal transduction pathway is recruited downstream of Syk after Fc RI activation (Fig. 5). For example, a rise in Ca 2 concentration and activation of PKC leads to maximal secretory activity [140], whereas activation of PLA2 for release of arachidonic acid is dependent on MAPK activation [28]. Activation of the MAPK-PLA2 pathway in RBL-2H3 cells has been clearly shown to depend on Syk, probably through the GDP/GTP exchange factor Vav [27]. The link between Fc RI and MAPK may also be through Shc, which is phosphorylated by Syk and then binds to Grb2. This adaptor protein associates with Sos to activate Ras upstream of MAPK [29] (Fig. 5). Because of PLC activation [131], it has always been thought that Fc RI-mediated calcium release is mediated by the second messenger IP 3. However, direct measurements in RBL-2H3 cells showed that IP 3 levels were relatively modest for the level of calcium released upon Fc RI activation. Recent data show that Fc RI clustering on the membrane of mast cells activates sphingosine kinase and produces sphingosine-1-phosphate, which is another second messenger for calcium mobilization [141, 142]. A sphingosine analog blocked the enzyme and the Fc RI-mediated calcium signal, but left Syk activation intact [87]. These data show that Fc RI principally utilizes a sphingosine kinase pathway to mobilize calcium [87] (Fig 5). ROLE OF FcR IN INFLAMMATION AND IMMUNITY DEFINED BY STUDIES WITH FcR-DEFICIENT MICE Fig. 5. Signal transduction pathways from Fc RI. Schematic representation of the biochemical routes activated by Fc RI in mast cells. Lyn is associated with the chain in the inactive receptor. On cross-linking, Lyn gets activated, probably under regulation of the phosphatase CD45, and both - and -chains become tyrosine phosphorylated. Syk then binds to the phosphorylated ITAM in the -subunit and also becomes activated. Syk, probably through the GDP/GTP exchange factors Vav or Shc/Grb2/Sos, activates the Ras, MAPK, PLA2 pathway to finally liberate arachidonic acid. PLC is also phosphorylated by Syk to produce DAG and activate PKC, which is involved in release of secretory granules. Sphingosine kinase (SK) is activated in a Syk-dependent manner to produce sphingosine-1-phosphate (S1P), a second messenger responsible for calcium release. IP 3 does not seem to play a major role in calcium mobilization after Fc RI clustering. Previous sections show the tremendous advance that has been made in understanding FcR biology. There is no doubt that they are the bridge between the humoral and cellular arms of immune defenses. But, despite several functions known to be triggered by these receptors (Table 1), their particular roles in vivo remain poorly defined. Recently, another experimental approach to study FcR function, namely gene disruption, has given very interesting insights into the role of these receptors in inflammation and immunity. As indicated earlier, mast cell degranulation via IgE crosslinking is responsible for allergic reactions, also known as type I hypersensitivity [143]. To explore this response in vivo, Fc RI was eliminated in mice by deleting the -chain of the receptor [144]. Similarly, the FcR -chain was deleted in mice by homologous gene replacement, resulting in animals that were not able to express Fc RI, Fc RIII, and Fc RI [98]. With the help of these FcR-deficient mice, the prominent in vivo role of Fc RI in allergic responses was confirmed because these animals were incapable of developing either cutaneous or systemic anaphylaxis to IgE-mediated activation [98, 144]. However, animals with their IgE gene disrupted, although incapable of producing this type of immunoglobulin, retained their capacity for presenting systemic anaphylaxis when challenged by antigen [145]. This anaphylactic response is likely to be mediated by IgG. These data confirmed that IgE crosslinking on the surface of the mast cell is the critical initial step for type I hypersensitivity, but in addition it suggested that IgG immune complexes play a role in this type of response [146]. IgG immune complexes are also responsible for triggering inflammation. By depositing on cell surfaces they cause the type III hypersensitivity reactions of inflammation [147]. IgG immune complexes, complement, and neutrophils are all 528 Journal of Leukocyte Biology Volume 63, May 1998

9 important for eliciting this inflammatory reaction. The mechanism described for this response is that complement directly binds to immune complexes and is then activated [148]. Then, complement products (such as anaphylatoxins C3a and C5a) initiate and amplify inflammation by recruiting leukocytes. Supporting this mechanism is the fact that complementdeficient animals had a reduced Arthus reaction, the reaction used as a model for type III inflammation [147, 149]. In this model, complement is responsible for inflammation and then tissue damage is caused by activated neutrophils, which liberate inflammatory mediators and proteolytic enzymes. FcRs do not seem to have a direct role in this response. However, when type III inflammation was tested in the -chain-deficient mice [98], it was found that they do not present an Arthus reaction [150], even though they have an intact complement system. Edema, hemorrhage, and neutrophils were all absent. The lack of neutrophils suggested that Fc Rs have an important role in initiating inflammation and in neutrophil chemotaxis. Moreover, type II hypersensitivity reactions, where cytotoxic self-reactive antibodies cause complement activation on tissues [147], were also significantly reduced in these animals [151]. These data show there is a fundamental role for FcRs in initiating inflammation, which was not recognized before. To test this idea, mice deficient in complement components C3 and C4 were analyzed with two inflammation models: a reverse passive Arthus reaction and immune hemolytic anemia. These animals showed similar types II and III inflammatory responses to wild-type control animals [152], supporting the idea that activation of Fc R, but not complement, is necessary for IgG-triggered inflammatory responses. The Fc R responsible for activating neutrophil chemotaxis and this type of inflammation is Fc RIII [153], and the cell type involved seems to be the mast cell, as indicated by the reduced Arthus reaction presented by the white-spotting (W) mast cell-deficient mice [154] and by differential reconstitution experiments in vivo [153]. The mechanisms by which IgG immune complexes initiate neutrophil chemotaxis and how the mast cell participates in this activation will become exciting new lines of research. Similarly to the -chain-deficient mice (which lack Fc RI, Fc RIII, and Fc RI), Fc RII has also been eliminated by gene disruption. Mice that have lost expression of this receptor are now providing new clues as to how Fc RII functions in vivo. These animals showed elevated immunoglobulin levels in response to both thymus-dependent and thymus-independent antigens, and also an enhanced passive cutaneous anaphylaxis reaction. The latter seems to be due to a lower threshold for Fc RIII-mediated mast cell activation [155]. Fc RIIB has clearly been shown to inhibit B cell activation, but these new data also indicate that Fc RII has a dampening function over a wide range of immune responses. So, Fc RII, in addition to its cellular functions, has a general negative regulatory function over immune complex-mediated activation of immune mechanisms in vivo. It is becoming clearer that Fc Rs have a more relevant role in the development of the immune response. The Fc Rdeficient mice are also helping to understand the role of these receptors in T cell development and function. Previously, it was shown that 14- to 17-day thymocytes express Fc RIII before the appearance of CD4, CD8, or TCR [156]. These cells develop into CD4 and CD8 T cells if they remain in the thymus, and into NK cells if removed from it. It was thought that Fc RIII may provide a developmental signal for T cell differentiation. However, -chain-deficient mice present normal thymic and peripheral T cell populations [98]. In contrast, -chain-deficient mice present marked alterations in thymocytes and peripheral T cells [146, 157]. Thus, although the role of Fc RIII on thymocytes remains unresolved, the -chaindeficient mice showed alterations in another population of lymphocytes, namely the intestinal intraepithelial lymphocytes (i-iel). These lymphocytes localized to the epithelium of the gut appear in the following two populations: thymic-dependent cells, expressing TCR and CD8, and thymic-independent cells, expressing either TCR or TCR but not CD8 [158]. The CD8 TCR i-iels [159] and also the CD4 /CD8 double-negative TCR thymocytes [160] showed a markedly reduced TCR expression. Analyzing the functional changes in these cell populations will provide new clues as to the role of FcR in regulating immune cell function in different tissues. CONCLUSION Hematopoietic cells express more than one isoform of Fc receptors. For this reason defining particular functions and signals for individual Fc Rs has been difficult. Several experimental systems have contributed tremendously to establish a general model for the initial molecular events of FcR signaling. Cross-linking of FcRs on the cell membrane by multivalent antigens triggers signaling, which initiates with the activation of the Src gene family tyrosine kinases associated to the inactive receptors. These kinases phosphorylate important tyrosine residues within the ITAM contained in the cytoplasmic tails of the receptor itself or its associated chains. Tyrosine phosphorylated ITAMs become docking sites for SH2-containing tyrosine kinases of the Syk and ZAP-70 families, which then are activated at this site [11] (Fig. 2). Syk kinase seems to be the central kinase for most FcR signal pathways. After Syk activation a series of different substrates have been identified in the various cell types and stimulation conditions, as well as the particular FcR involved (Fig. 3 and Fig. 5). In the case of phagocytosis, for example, we see that each human Fc Rinthe absence of other Fc Rs is capable of mediating phagocytosis, but with particular requirements. It is then becoming clear that although the various isoforms of Fc RI, Fc RIIA, Fc RIIIA, and Fc RI use phosphorylated ITAMs as binding sites for other cytoplasmic molecules, the composition of the signaling complexes formed by distinct receptors are indeed different. ITAMs and ITIMs are now being described to have particular specificities for different SH2 domain-containing enzymes [100, 101]. The molecular complexes created by each receptor isoform are responsible for activating different biochemical pathways. The characterization of the molecular structure of all FcRs and the identification of tyrosine phosphorylation of ITAMs as the initial step for signaling represent major advances in our understanding of FcR biology. The next step in discerning the Sánchez-Mejorada and Rosales Fc receptor signal transduction 529

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