Towards an isotypic network

9 ELSEVIER

Paris

A n n . Insl. Pasleur / h m n u n o l .

1985

1985, 136 0, 383-437

7e F O R U M D'IMMUNOLOGIE

Fc RECEPTORS AS R E G U L A T O R Y MOLECULES

For this Immunology Forum, devoted to Fe Receptors ( F e R ) , we have invited a restricted number of investigators to briefly summarize their own view of F c R as regulatory molecules. Their conlributions constitute the present Forum, which, is presented as follows. The first three papers are general overviews on the topic. The five subsequent papers address more specifically the issue of isotgpic regulation. They are followed by three papers discussing the mechanisms of FcR-mediated activation/inactivation of K cells and B ceils. The F o r u m finally doses with an outside view of the i m m u n e system through turnout cell FeR, and opens itself up to discussion.

Marc DaCron and Wolf H. Fridman

TOWARDS AN ISOTYPIC NETWORK b y M. DaCron and W. H0 Fridman Laboraloire d'Immunologie Cellulaire el Clinique, I N S E R M . U255, I n s l i l u l Curie, Paris

Fc receptors (FcR) are molecules capable of interacting with the Fc portion of immunoglobulins. This somewhat tautological definition actually encompasses three intricate notions. Their specificilg is what distinguishes FcR from the many other receptors. The interaction is initiated by the c~recognition ~, of limited portion(s) in the C-terminal domains of the heavy chains of immunoglobulins. B i n d i n g depends on affinity, which steadily maintains the reversible F c / F c R interaction in a right configuration for at least a

measurable period of time. Signaling is, under appropriate conditions, the consequence of the constraint thus imposed on FcR. It triggers what ultimately results in a detectable biologic effect. Altogether, these three notions not only provide a convenient functional definition of FcR; when analysed in more detail, they underline several significant aspects of FcR t h a t may not be immediately apparent. Eventually, they might help to better delineate the regulatory role we believe FcR are endowed with.

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F c R have widespread d i s t r i b u t i o n . They are expressed on B and T lymphocytes, on K and N K cells, on macrophages and on the effector cells of inflammation (mast cells, all three types of polymorphonuclear leukocytes, and platelets). They are expressed on a variety of epithelial and endothelial cells (trophoblast, blood vessels, enterocytes, m a m m a r y gland...) where they fulfill transport functions. They are expressed on cells with no apparent link with the immune system (sperm cells, goblet cells, hepatocytes..,). They are also expressed on cells which are potential targets of the immune system (tumour cells, parasites...). FeB are ubiquitous structures, conserved in ontogeny along m a n y differentiation pathways. In addition, FcR-like structures are borne by a variety of bacteria (staphylococci, streptococci, pneumococcl, Hemophilus in[luenzae). If one examines the specificity of F c B borne by these various cell types, one finds a striking heterogeneity. First, F c R for all known classes and subclasses of serum iminunoglobnlins exist. Second, several different FcR are co-expressed on a single cell. This was first observed for mouse, rat, guinea pig and h u m a n macrophages ll]. It also applies to mast cells [21 and basophils [3] and to T [4] and B cells 15]. It is probably a rule rather than an exception t h a t Fcl-I are not clonally expressed. Third, m a n y F c R have affinity for more t h a n one isotype. Thus, besides classspecific Fell for IgE, IgA and IgG3, FcR were described which bind several IgG subclasses and, in some cases, IgE. It follows that, on one individual cell, different FeR m a y recognize a single isotype. On rat [61 and mouse [5] peritoneal macrophages, and on rat basophilic leukaemia cells [71, IgE can bind to F e a r and to Fcy/r on aseitic hybridoma T cells, IgG1 and IgG2b bind to Fcy1/,(2bR and to Fc~-2a/v2b/y1R [8]. Fourth, different F e B bind to different sites of the immunoglobulin Fc portion. This holds for F e B expressed on different cell types and even for FeB borne by the same cell [1]. Reciprocally, F e B discriminate otherwise ignored hetero-

geneity within a single isotype. Thus, mouse m a s t cells are degranulated by immune complexes made with some monoclonal IgG2a antibodies but not with others [9]. Altogether, these four sets of observations indicate t h a t immunoglobulins are seen with different eyes not only by different cells, but by different FcR. If this is correct, one shonld substitute the notion of a large number of polymorphic F c B with a vast array of specificities for the commonly accepted notion of a limited number of FcR, each binding one class of immunoglobulin. It follows t h a t diversity is a characteristic which FcR might share, at least to some degree, with immunoglobulins. Another intriguing feature of F c R arises when one examines their phylogeny. Bacteria probably appeared before vertebrates acquired immunoglobulins. They nonetheless possess receptors for irnmunoglobulins which share m a n y properties with FcR borne b y eukaryotic cells [10]. Like m a m m a l i a n cells, they express receptors for most isotypes, the specificity of which differs from one strain to another. On one strain of streptococci, two separate receptors for IgA and IgG could be identified. Receptors of different bacteria bind to different sites in the Fc region. Besides such an analogous diversity, m a m m a l i a n and bacterial FcR have a comparable specificity among the different species. Staphglococcus aureus protein A (SPA) binds immunoglobulins of all m a m mals, but it has no affinity for bird, reptile, amphibian or fish immunoglobulins. Furthermore, F(ab')~ fragments of rabbit anti-SpA antibodies bind to F e B of human mononuclear cells [11], indicating at least some structural relationship. Whether such a similitude reflects common selective pressures or common origins, whether bacterial FcR preceded immunoglobulins in evolution or whether they were induced by the host environment are highly intriguing questions. Further in evolution, it is not clear whether an FcR exists for the lgMlike immunoglobulins of cartilaginous and bony fishes. However, as soon

R E G U L A T O R Y FcR as non-IgM 7S immunoglobulins appeared in Anuran amphibians, biologically active FeR for this isotype, apparently distinct from FoR for IgM, could be found [12]. At the same time, when IgG subclasses individualized, separate subelass-specilic FeB appeared in mammals [13], as if the ligand had diverged in parallel with the receptor during evolution. The possibility therefore exists that FeB were not shaped from immunoglobulins. The apparently self-evident conception of an oriented interaction in which immunoglobulins are the ligands and Fell are the receptors stems from the usual view of immunoglobulins as soluble proteins, whereas FeB are envisioned as cellular, membrane-bound structures. But memBrane immunoglobulins on B cells also expose Fe domains involved in binding to FeB. Besides, Fell-like molecules [14], sharing antigenic determinants with FcR [15, 161, are released by T cells. These imnmnoglobnlin-binding factors (IBF) selectively recognize IgG 117], IgE [18], IgA [19] or even IgG subclasses [20]. They can be detected as circulating molecules in normal serum and they bind to B-cell membrane immnnoglobulins of the appropriate isotype. Finally, it is well known that SpA has two forms. One is associated with the bacterial cell wall, while the other is actively secreted. Both have the same electrophoretic mobility, the same molecular weight, the sample pI and the same amino acid composition [10]. Both can bind to lymphocyte membrane immunoglobulins (and form rosettes when attached to erythrocytes) or to FcB-bound immunoglobulins (and induce histamine release by leukoeytes). Therefore, it is also evident that soluble FeB (IBF and SpA) can behave as ligands, and imnmnoglobulins as receptors. Fc and FeB are non-oriented complementary ligands. For a long time the biological signilicance of lymphocyte FcR was a matter of speculation. The general consensus, however, was that FeB should be linked to homeostatic processes. This was based on their des-

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cription on subsets of T lymphocytes endowed with regulatory properties, though no direct role could be assigned to FoR in these biologic activities. On the other hand, negative signals were shown to be delivered through FoR to B lymphocytes, and IBF released by activated T cells was demonstrated to suppress in vitro antibody responses [17]. During the past few years, evidence bloomed from several laboratories, supporting FcR as being key imnmnoregulatory molecules. Firsl, FeB expression was found not to be an ~ all or none ~ phenomenon under genetic control only. It depends on the extracellular environment. It increases upon mitogenie or allogeneic activation. Lymphokines, such as interferon [21], glyeosylation-regulating factors [18] or IgEinduced regulants [22], modify FeB expression on lymphocytes. But above all, imnmnoglobulins themselves were found to induce F e a r [18], F e a r [23], Fc~'R [8] and even F e a r [8] on several cell types including "T and B cells. Lymphocyte Fcll are not static differentiation markers ; they adjust themselves to variations in the concentration of their ~ natural ~ ligands. Interestingly, like hybridoma T cells which express more FcvR after passage in vivo as ascites [8], streptococci show an enhanced Fcll expression after infecting their hosts [24]. Second, upon interaction with T-cell FcR, immunoglobulins induce the secretion of IBF. IgE induces the secretion of IgE-BF (i. e. with a selective affinity for IgE) [18], IgA that of IgA-BF [19], lgG1 that of IgG1-BF, and IgG2 that of IgG2-BF [20]. [mmunoglobulins therefore can induce both the membrane and the secreted forms of FeR. Third, IBF interacts with B cells and regulates the production of antibodies in vilro [17]. Each isotype-specifie IBF selectively regulates the corresponding isotype. Thus, IgE-BF, IgA-BF, IgG1-BF and IgG2-BF, respectively, regulate the IgE [18], IgA [19], IgG1 and IgG2 [20] compartments of an antibody response. Fourth, IBF can regulate the membrane expression of immunoglobulins on B cells. Thus far, this was esta-

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blished only for IgE-BF, which inhibits the expression of IgE on B lymphocytes, plasma cells and IgE-seereting h y b r i d o m a B cells [25]. Therefore, F e b - r e l a t e d I B F can regulate both the secretion of antibodies and the expression of membrane immunoglobulins. The two complementary structures regulate each other. If we summarize what arose from our discussion of the three simple notions which we used to define F e b , the following points emerge. 1. - - Though F e b are polyclonally expressed on a variety of cells, they exhibit significant diversity in their specificity. They actually cover a much broader repertoire t h a n initially thought. This repertoire, i. e. the fine speeificities of the multiple F e b , remains to be delineated. 2. - - Immunoglobulins and F e b both exist either in a soluble form (secreted Ig, IBF, SpA) or as m e m brane-associated molecules (membrane Ig, F e b ) . They are two-way-complem e n t a r y structures. They can therefore conceivably establish 4 types of interactions: seer. Ig - - FcR

I

l

I B F - m b r . Ig 3. - - Experimental evidence was obtained t h a t at least the three followsing interactions have isotype-specifie regulatory consequences: (xa) seer. Ig -+ F e b ( S ) ( S ) I B F -+ mr. Ig ( ~ ) We therefore believe t h a t the necessary conditions are met for enabling the establishment of a regulatory network. As a working hypothesis, we propose t h a t an isotypic network might stand next to the idiotypic network. Though not directly crossreacting, the two networks could be connected via immunoglobulins which have the capacity to be engaged in both idiotype/anti-idiotype and Fc/FclR interactions. In addition, the simultaneous presence of idiotypes and anti-idiotypes, of isotypic deter-

minants and of several FcR oil individual cells, would further intricate the two lattices. An isotypic network would primarily reflect a physiological autoreactivity, with all necessary elements being contained within the immune system. As such, it would constitute another ,~ hall of mirrors ~ [26] and it would have no requirement for an external image to be moulded in. Because of FcR ubiquity, however, an isotypic network would extend far beyond the bounds of the immune system. Within the organism, it would be connected to F e b + cells of other systems. Outside, it would enable FcR-bearing pa~'asites and bacteria to interact with the immune system, even before an immune response has been initiated. If one accepts t h a t pathological situations m i g h t be exaggerations of normal mechanisms, evidence for an isotypic network m a y be as follows. In Nipposlrong!llus-brasiliensis-infected rats, IgE production is regulated b y I g E - B F produced b y FcR + T cells upon stimulation b y IgE [18]. In IgAmyeloma-bearing mice, a population of Fc~I1 + T cells expands which can suppress IgA production [27]. In IgA defciencies, decreased numbers of F e a r + cells are observed which can be induced b y IgA under appropriate conditions [28]. In normal situations, a steady state would actively be maintained. This might explain why the concentration of the various classes of immunoglobulins is among the m o s t stable parameters in normal serum.

Re/erences.

[1] UNKELESS, J.

C., FLEIT, H. ~,~ MELLMAN, I. S., Advanc. Immunol., 1981, 31, 247. [2] DAERON, M., PROUVOST-DANON, A. & VOISIN, G. A., Celt. Inununol., 1980, 49, 178. [3] ISIIIZA-KA, T., STERK, A. & ISHIZAKA, K., d. Immunol., 1979, 123, 578. [4] DAERON, M., YODOI, J., NEAUPORT-SAuTES, ~., MONCUIT, d. & FRIDMAN, \V. H., Europ. J. Immunol., 1985, 15 (in press).

R E G U L A T O R Y FcR

[5] DAERON, M. & ISHIZAKA, I~., d. Immunol., 1985. [6] BOLTZ-NITULESCU, G., BAZIN, H. & SPIEGELBERG, H., d. exp. Med.,

1981, 154, 374. [7] SEGAL, D. M., SHABBOW, S. 0., JONES, J. F. & SIRAGANIAN, R., J. Immunol., 1981, 126, 138. [8] DAERON, M., NEAUPOBT-SAuTES, C., YODOI, J., MONCUIT, J. & FRIDMAN, W. H., Europ. J. lmmunol., 1985 (in press). [9] DAERON, M., COUDERC, J., YENTUBA, M., LIACOPOULOS, P. & YoISIN, G. A., Cell. lmmunol., 1982, 70, 27. [10] LANGOX'E,J. J., Advanc. lmmunol., 1982, 32, 157. [11] BIGUZZI, S., Europ. J. lmmunol., 1979, 9, 52. [12] SEKIZA~'A, A., FUJII, T. & TOCHINAI, S., J. Immunol., 1984, 133, 1431. [13] HAEFFNER-CAYAILLON, N., KLEIN, M. & DORRINGTON, K. J., J. Immunol., 1979, 123, 1905. [14] GISLEB, R. H. & FRIDMAN, W. H., J. exp. Med., 1975, 142, 507. [15] HUFF, T. F., YODOI, J., UEDE, T. & ISHIZAKA, K., J. Immunol., 1984, 132, 406. [16] DAERON, M., NEAUPORT-SAUTES, C., MONCUIT,,J. & FRIDMAN, W. H., Fed. Proc., 1984, 43, 1969. [17] FRIDMAN, ~V. H., RABOUBDINCOMBE, C., NEAUPORT-SAUTES, C. & GISLER, R. H., Immunol. Rev., 1981, 56, 51.

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[18] ISHIZAKA, K., Ann. Rev. Immunol., 1984, 2, 159. [19] YODOI, J., ADACIII, ~1., TESHIGAWARA, K., MYAMAINABA, M., MASUDA, T. & FRIDMAN, W. H., J. Immunol., 1983, 131, 303. [20] LowY, I., BREZIN, C., NEAUPORT-SAUTES, C., THI~ZE,J. & FRIDMAN, W. H., Proc. nat. Acad. Sci. (Wash.), 1983, 80, 2323. [21] FRIDMAN, W. H., GRESSER, 1., BANDU, M. T., AGUET, M. & NEAUPORT-SAUTES, C., J. Immunol., 1980, 124, 2436. [22] MABCELLETTI, J. & KATZ, D. H., J. Immunol., 1984, 133, 2821, 2829, 2837, 2845. [23] YODOI, J., ADACHI, M. & MASUDA, T., J. Immunol., 1982, 128, 888. [24] REIS, K. J., YARNALL, M., AYOUB, E. M. & BOYLE, M. D. P., Scan& d. Immunol., 1984, 20, 433. [25] UEDE, T., HUFF, T. F. & ISHIZAKA, K., J. Immunol., 1984, 133, 803. [26] JERNE, N. K., Immunol. Bey., 1984, 79, 5. [27] HOOVER, R. G., DIEKGREFE, B. K., LAKE, J., KEMP, J. D. & LYNCH, R. G., d. Immunol., 1982, 129, 2329. [28] ADACItI, M., YODOI, J., MASUDA, T., TAKATSUKI, K. & UCHINO, H., J. Immunol., 1983, 131, 1246. We thank Sebastian Anfigorena for wild ideas and passionate discussions.

R O L E OF F c - R E C E P T O R - B E A R I N G CELLS IN I S O T Y P E - S P E C I F I C R E G U L A T I O N OF A N T I B O D Y S Y N T H E S I S by J. F. Marcelletti, P. del Guercio and D. H. Katz Medical Biology Inslilule, 11077 North Torreg Pines Road, La Jolla, CA 92037 ( U S A )

In this short discussion, we propose a working hypothesis which can describe the mechanism b y which immunogtobulin-binding factors (IBF), cell surface Fc receptors (FcR) and Ig can function in concert as elements in the regulation of cellular interactions in the immune system. In addition to their known specificity of binding to

the Fc portion of particular isotypes of antibody, I B F have historically been defined by virtue of their ability to modulate, in an isotype-specific manner, the synthesis of antibody b y acting directly on antibody-producing B cells [1-4]. However, I B F m a y also have the capacity to modulate immunoglobulin synthesis independently of