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A concept of immune regulation of somatic cell differentiation
J. theor. Biol. (1984) 107, 443-456
A Concept of Immune Regulation of Somatic Cell Differentiation V. G. NESTERENKO
Laboratory of Immunological Tolerance, Gamaleya Institute of Epidemiology and Microbiology, U.S.S.R. Academy of Medical Science, Gamaleya St. 18, Moscow 123098, U.S.S.R. (Received 8 November 1982, and in revised form 11 October 1983) On the basis of several lines of experimental evidence a hypothesis is advanced on autoimmune regulation of somatic cell differentiation in an immunologicallymature organism ("self-anti-self"hypothesis of differentiation). There are supposed to be clones of lymphocytes interacting via their antigen-recognizing receptors with autologous differentiation antigens on various target cells. This interaction would modify the genetically determined rate of cell differentiation. Some implications of the hypothesis are discussed in relation to immunological memory, tolerance etc. In particular, the new concept might imply similarity (or identity) of the genes coding for autologous differentiation antigens and those responsible for the idiotypes of antigen-recognizing lymphocyte receptors. The key function of adult lymphoid tissue is understood to be generation of immune responses to various antigens (antigens of cell mutants, microbial and viral antigens etc.). These responses maintain homeostasis and stability of the antigenic structure of the internal milieu (Burnet, 1959, 1969; Brondz & Rokhlin, 1978). An immune response to unmodified autologous antigens is usually considered pathological (Burnet, 1959, 1969; Weigle, 1975; Stobo & Loehneu, 1976; Fontalin & Pevnitsky, 1978). Yet there are observations indicating that immune responses to some autoantigens are not abnormal but may be regarded as an essential step in lymphocyte differentiation (Jerne, 1971; Zinkernagel & Doherty, 1977; Zinkernagel et al., 1978; Benacerraf, 1980). Here a hypothesis is advanced which proposes that the immune response to a number of autoantigens supports differentiation not only of lymphocytes but also of other target cells. The term "differentiation antigen" is used below to designate surface antigens formed on cells at a certain stage of development and disappearing during further differentiation. The present hypothesis assumes the existence of lymphocytes capable of interacting via their antigen-recognizing receptors with differentiation anti0022-5193/84/070443 + 14 $03.00/0
© 1984 Academic Press Inc. (London) Ltd.
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gens of various autologous somatic cells. Such interaction modifies the genetically determined rate of cell differentiation. No tolerance is acquired to autologous differentiation antigens, since their concentrations are usually variable and low (too low also for induction of tolerance based on clone deletion or suppression), and only sometimes exceed a certain threshold which provokes the response of lymphocytes. Let us suppose (Fig. 1) that a clone of anti-A1 lymphocytes interacts in vivo with somatic cells carrying differentiation antigen A1. As a result, the transition of cells from functional state A I to state A2 (marked by differentiation antigen A2) is either accelerated or delayed. Subsequently the receptors of an anti-A2 lymphocyte clone will react specifically with differentiation antigen A2 modulating the speed of transition to functional state A3 (marked by differentiation antigen A3) and so on. In the light of this hypothesis, antigen-recognizing receptors (or antibodies) may be considered a kind of differentiation "hormones". Further on, for the sake of simplicity, only those situations will be discussed when transition to another functional state is accelerated by the contact between antigen-recognizing receptors and differentiation antigens. Naturally, a delayed transition can also occur. My hypothesis is based on eight lines of evidence reported in the relevant literature: (1) changes in the spectrum of surface antigens accompanying cell differentiation; (2) existence of lymphocytes potentially capable of responding to autologous antigens; (3) recognition of autologous antigens of the major histocompatibility complex (MHC) by T-lymphocyte receptors; (4) existence of an autologous idiotype-anti-idiotype network; (5) regulation of the differentiation of somatic cells by antibodies to their surface antigens; (6) discovery of morphogenetic lymphocyte activity; (7) effect of thymectomy on the rate of reparative events; (8) antigenic and/or structural homology between Ig and some cell surface antigens and regulatory molecules. Below, all this evidence will be discussed in detail. (1) Various cell transformations are known to be accompanied by the appearance of new surface antigens. Thus, during proliferation, cells exhibit antigens which cannot be detected on resting cells (Thomas & Phillips, 1973; Thomas, 1974; Bluming et al., 1975; Feeney & H/immerling, 1976; Nesterenko & Kovalchuk, 1976; Nesterenko & Gruner, 1980; Nesterenko, Novikova & Fontalin, 1980). In early phases of differentiation the antigenic structure of granulocytes differs from that of mature cells (Winchester et al., 1977). T- and B-tymphocytes acquire dissimilar and specific antigens as they evolve from the stem cell (Raft, 1971; Niederhuber, Britton & Berguist, 1972; Cantor & Boyse, 1977). Effector cells involved in immune responses possess antigens which are absent on less differentiated lym-
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phocytes (Takahashi, Old & Boyse, 1970; Sullivan, Berke & Amos, 1973; Kimura & Wigzell, 1977; Nesterenko et al., 1980). When thymocytes differentiate into T-lymphocytes, F9 antigen is replaced on their surface by H-2 antigens, and TL antigens are replaced by Qa-2 antigens (Vitetta et al., 1975; Michaelson etaL, 1977). This list of examples is far from complete, but it is sufficient to demonstrate the variability of surface antigens and their dependence on cell differentiation stages. (2) The autologous system has been shown to contain lymphocytes with a potential capacity of responding to a number of antigens which are usually in contact with them in vivo: immunoglobulins (Ig) (Herzenberg, Okumura & Cantor, 1976; Rodkey, 1976; Cosenza, Augustin & Julius, 1977; Owen, Ju & Nisonoff, 1977; K6hler, Richardson & Smyk, 1978), DNA and RNA (Tatal, 1976; Sawada et al., 1977), antigens on erythrocytes (Cox & Keast, 1973; Gleichmann & Gleichmann, 1976; HammarstrSm et al., 1976; Yamashita et aL, 1976), on thymus cells and T-lymphocytes (Shirai, Yoshiku & Mellors, 1972; Bretscher, 1973; Fugi & Milgrom, 1973; Auer, Tomas & Milgrom, 1974; Zinkernagel et al., 1978), on B-lymphocytes (Opelz et al., 1975; Kuntz, Innes & Weksler, 1976; Weksler & Kozak, 1977). There are also lymphocytes capable of responding to antigens of the myocardium (Kaplan & Meyeserian, 1962; Lyampert & Danilova, 1975), those of the hepatic (Eddleston & Williams, 1974), renal (Vyazov & Barabanov, 1973; Borel, Lewis & Stollar, 1973), splenic tissues (Howe, 1973), lymph node endothelium (Andersson & Andersson, 1976), antigens on macrophages and reticulocytes (Steinman & Witmer, 1978) and other cell-associated antigens (von Boehmer & Byrd, 1972; Cohen & Wekerle, 1973; Ponzio, Fink & Battisto, 1975; Ching, Marbrook & Walker, 1977; Peck et al., 1977; Gozes et al., 1978; Miller & Kaplan, 1978). (3) T-lymphocytes have been found to carry receptors recognizing the autologous antigens of MHC (Zinkernagel & Doherty, 1977; von Boehmer, Haas & Jerne, 1978; Benacerraf, 1980). (4) The immune response to idiotypic antigenic determinants of autologous Ig or cellular antigen-recognizing receptors is supposed to be a normal event regulating the development of a given idiotype and, consequently, the functioning of idiotype-positive lymphocytes (Rowley et al., 1973; Jerne, 1974; Hoffmann, 1975; Richter, 1975; Binz & Wigzell, 1977; Hiernaux, 1977; Nesterenko & Chernyakhovskaya, 1977; Woodland & Cantor, 1978; Kraskina, 1979; Nesterenko et al., 1982). (5) Somatic cell differentiation can be regulated in various animal models by antibodies produced experimentally to components of the cell surface. Antibodies are known to mediate killing of target cells by complement. It has also been established that they can block cell differentiation at a certain
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stage. Thus, Fab fragments of rabbit antibodies to F9 antigen, when added to mouse embryo cultures 32 to 36 hours after their initiation, did not influence cell cleavage but prevented the formation of a compact morula and blastocyst. This effect was reversible: the blastocyst could be formed if incubation was continued after removal of the antibodies. Moreover, washed embryonal cells which had been transferred to pseudopregnant females gave rise to normal progeny. When the stage of the blastocyst was attained, the cells lost sensitivity to the blocking action of the antibodies (Kemler et al., 1977). Trenkner & Sarkar (1977) showed that addition of antibodies against polysaccharide antigens to cultures of murine cerebellar cells suppressed reversibly their differentiation. If antibodies were washed off within one or two days, differentiation was resumed. On the other hand, a number of investigators reported a stimulating effect of antibodies on proliferation and morphogenesis. As early as 1901, Mechnikoff found that small amounts of cytotoxic sera, in contrast to large doses, increased the functional and proliferative activities of the target organ. Experiments done in vivo and in vitro demonstrated a marked growth-promoting effect of anti-reticular serum on tissues of mesenchymal origin (Bogomolets, 1956). Rodionov & Korol (1963) described enhancement of proliferative processes in the livers of animals injected with anti-hepatic serum. Ardry, Courtin & Thu (1966) showed that antisera against osseous and cartilaginous tissues stimulated repair of bone fractures. Both anti-lymphocyte sera (Woodruff, Reid & James, 1967; Falcott, Oriol & Iscaki, 1972; Weber, 1977) and anti-Ig antibodies (Maino, Hayman & Crumpton, 1975; Bell & Wigzell, 1977; Sidman & Unanue, 1978) induced proliferation of lymphocytes. Several studies revealed a stimulating action of anti-idiotype antibodies on idiotype-positive lymphocytes (Eichmann & Rajewsky, 1975; H~immerling et al., 1976; Frischknecht, Binz & Wigzelt, 1978; Binz, Frischknecht & Wigzell, 1979; Ramseier, 1979). Shearer, Philpott & Parker (1975) observed enhanced proliferation of L-cells after treatment with a small amount of specific antibodies. (6) There are reports describing morphogenetic activity of lymphocytes, i.e. their capacity to influence differentiation of autologous (or syngeneic) somatic cells. A modulating effect on differentiation of syngeneic hemopoietic stem cells is a well-documented property of T-lymphocytes (Golovistikov, Petrov & Khaitov, 1970; Kitamura, Kawata & Kanamaru, 1972; Goodman, Basford & Shinpock, 1975). In many experiments the functional state of non-lymphoid somatic cells of a donor animal could be transferred with its lymphocytes to a syngeneic recipient. Thus, viable spleen lymphocytes taken from partially hepatectomized mice induced high proliferative activity of parenchymatous and reticulo-endothelial cells in the livers
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of intact animals. The mitotic index in salivary glands and renal tubular epithelium of the recipients remained unaltered and was slightly increased in renal connective tissue (to a much lesser extent than in liver cells). On the other hand, transfer of lymphoid cells isolated from murine spleens after unilateral nephrectomy led to an insignificant increase in the mitotic index of liver reticulo-endothelial cells but markedly augmented that of renal tubular epithelium (Babaeva, Kraskina & Liozner, 1969a, b). Subsequently it came out that the capacity of transmitting the stimulus to proliferation resided in T-lymphocytes (Babaeva, Kraskina & Udina, 1980). Similar results were obtained by Fox & Wahman (1968), Pilskin & Prehn (1975), Radosevic-Stasic & Rukavina (1979). Using lymphocytes from affected donors, Warnatz et aL, (1967) and Kolpaschikova (1978) reproduced in normal syngeneic recipients certain changes typical for hepatitis caused by carbon tetrachloride or a homogenate of allogeneic liver. SvetMoldavsky, Schvasabaya & Zinzar (1974) observed cardiomegaly in mice injected with lymphoid cells from syngeneic donors whose hearts had hypertrophied due to experimental aortic stenosis. A rise in blood sugar level was recorded in recipients of T-lymphocytes from syngeneic mice with streptozotocin-induced diabetes (Buschard & Rygaard, 1978). Spleen cells from mice with osteopetrosis could provoke the disease in intact syngeneic animals (Walker, 1975). In Dolgushin's experiments (1978) transfer of lymphoid cells from syngeneic donors stimulated the healing of skin burns in irradiated recipients. This effect was especially pronounced if the donors also had burns. Interestingly, Babaeva, Nesterenko & Udina (1982) showed that lymphocytes from mice twice subjected to partial hepatectomy had a greater ability to enhance proliferation of liver cells in intact recipients as compared to those from the survivors of a single operation. This observation calls to mind the well-known phenomenon of the development of immunological memory during the primary response to a foreign antigen. (7) According to a number of authors, thymectomy changes the rate of repair after experimental injuries. Thus, Averchenko & Movshev (1969) studied bone regeneration in rats thymectomized upon reaching maturity. The incorporation of radioactive calcium into regenerating (and normal) bone tissue was considerably lowered in these animals, especially" if regeneration took place after repeated injury. Several investigators (Davies et al., 1964; Dukor & Miller, 1965; Forabosco & Toni, 1969; Babaeva, 1972) came to the conclusion that thymectomy inhibited proliferative processes in the regenerating liver. An opposite opinion was expressed by Aufiero et al. (1964), who insisted that regeneration of the liver was more complete in rats subjected to adult thymectomy than in control animals. It would be difficult to propose an
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explanation of such discrepancies. Of paramount importance is the fact that thymectomy alters the rate of organ and tissue repair, and as for the direction of the changes, it might depend on the particular experimental conditions. These data possibly suggest involvement of the immune T-system in reparative events. (8) According to Coligan et al. (1981), H-2 antigens and Ig have homologous amino acid sequences. Homology in the structure of Ig and that of Thy-1 antigen has been detected by Cohen et al. (1981). Moreover, Thy-1 antigen has been shown to share antigenic determinants with the V region of the light chain in Ig (Pillemer & Weissman, 1981). Hormoneproducing ceils of the anterior pituitary have been found to carry surface Ig (Pouplard etal., 1976; Boyd, Peters & Morris, 1978), which are supposed to influence their functional activity. Moreover, common antigenic characteristics have been detected in Ig and several pituitary hormones. Thus, precipitation lines of identity could be observed between the luteinizing, follicle-stimulating, thyrotrophic and gonadotrophic hormones, and IgG antigenic determinants, as well as between the gonadotrophic and thyrotrophic hormones, and IgA determinants. The significance of these observations in relation to my hypothesis will be clarified below. The model of target cell differentiation under the action of autologous lymphocytes, which is outlined in Fig. 1, implies the occurrence of the following events. (a) Lymphocytes from a donor whose somatic cells are in a certain functional state can transmit this state to syngeneic recipients. Thus, transfer of anti-Ak lymphocytes would accelerate the transition of non-lymphoid somatic cells from state Ak to Ak÷~.
!
t anti-A~
2
T onti-Az
3
T anli- A3
~
T anti- Ak
n-1
n
1 anti- An- 1
FIG. 1. Immune regulation of target cell differentiation. A~, A2, Aa, Ak, A._1, An= differentiation antigens of target cells in states A1, A2, m 3, Ak, An- 1 and A, respectively. ~, direction of the interaction of lymphocyteswith autologous differentiation antigens. direction of target cell differentiation.
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HYPOTHESIS
(b) Autologous differentiation antigens can elicit a secondary immune response. Consequently, state Ak÷l would develop more rapidly in syngeneic recipients if they receive lymphocytes from a donor with state Ak created repeatedly and not for the first time. (c) Immunological non-responsiveness to differentiation antigens, for instance, to antigen Ak, can be induced artificially. In such a case transition from state Ak tO Ak+~ would be delayed. Tolerance of a suppressive type could be transferred with donor lymphocytes to an intact recipient. If tolerance in a donor animal results from anti-Ak clone deletion, its lymphocytes would fail to influence the recipient's somatic cells exhibiting state
Ak. A prerequisite for interaction of anti-Ak lymphocytes with differentiation antigen Ak (as for immune responses of all other types) is probably the presence of the antigen in a certain threshold concentration. The number of target cells carrying antigen Ak decreases when they are stimulated to attain the functional state associated with antigen Ak+~.However, the model shown in Fig. 1 does not provide for any direct immune interactions that would alter the level of antigen Ak with a rise in antigen Ak÷~, i.e. it has no feedback. Another version of this model comprising a feedback system is depicted in Fig. 2. Let us suppose that differentiation antigen Ak-1 and
t
t
l
onti-,~ I
onti-Zt 2
anti-A 3
ctnti-,~k. 1
t
t
anti-~ k
anti-A n
FIG. 2. A modelof immuneregulationof target cell differentiationcomprisinga feedback system. Shaded structures are idiotypicantigenic determinants. For other designationssee legend to Fig. 1. the idiotype of anti-Ak lymphocyte receptors have identical (or similar) determinants. Therefore the antigen-recognizing receptors of anti-Ak-1 lymphocytes will interact with the latter idiotype, as well as with antigen Ak-1. In such a case the transition from state Ak-~ tO Ak brought about by the interaction of antigen Ak-~ with anti-Ak_~ lymphocytes will not only
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augment the number of cells carrying antigen Ak, but also be accompanied by a response of anti-Ak-2 lymphocytes to the high level of anti-Ak-~ idiotype. The resulting rise in the level of anti-Ak-2 idiotype will probably enhance its interaction with antigen Ak-2 and abrogate (or weaken) the response of anti-Ak-~ idiotype to antigen Ak-1. Consequently, the cells that have remained in state Ak-2 would attain state Ak-i m o r e rapidly. According to the model presented in Fig. 2, the immune response of anti-Ak lymphocytes to antigen Ak will suppress anti-Ak+l lymphocytes (since anti-Ak lymphocytes interact with anti-Ak÷1 idiotype) and stimulate anti-Ak_l lymphocytes (which respond to anti-Ak idiotype). This will accelerate the transition of target cells from state Ak t o Ak+l and from Ak-1 tO Ak, and delay the transition from Ak+1 t o Ak+2. Induction of immune non-responsiveness to antigen Ak will result in opposite changes: transition from state Ak t o Ak+t and from Ak-! to Ak will be delayed, while transition from Ak+l t o Ak+2 will proceed faster. If the model of Fig. 2 is valid, anti-differentiation antibodies would be active not only against their differentiation antigen, but also against the idiotype of the lymphocytes recognizing the next antigen in the sequence of target cell differentiation, while anti-idiotype antibodies would interact with the first antigen. Thus, lymphocytes from partially hepatectomized mice would fail to transmit high mitotic activity to the recipient's hepatic cells after treatment in vitro with antibodies directed against the antigens of regenerating liver (anti-differentiation antibodies) in the presence of complement. On the other hand, absorption of anti-idiotype serum with antigens of regenerating liver would eliminate antibodies directed against the idiotype of the donor lymphocytes. It should be noted that model 2 implies an intimate relationship between the genes coding for the idiotypes of lymphocyte receptors which recognize autologous differentiation antigens, and the genes responsible for the synthesis of the latter. They constitute a single group, but not two distinct classes. Each gene of the group can code both for the recognizing structure and for what is being recognized. It may be assumed that only this strictly limited set of genes is subject to hereditary transmission, while all the diversity of antigen-recognizing receptors is generated during ontogeny by mutations, recombinations or similar events in V-genes of lymphoid cells proliferating under the influence of autologous differentiation antigens. Direct experiments which would validate model 2 have yet to be designed. However, there is some preliminary evidence that provides credence for this model: (a) homology of the structure of H-2 antigens and that of Ig (Coligan et al., 1981); (b) antigenic and structural similarities between Ig and Thy- 1 antigens (Cohen et al., 1981; Pillemer & Weissman, 1981); (c)
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451
HYPOTHESIS
the common antigenic characteristics found by Pouplard el aL (1976) and Boyd et al. (1978) in Ig and several hormones (which could act as differentiation antigens on the surface of hormone-producing cells), and (d) abundant data about the regulatory role of idiotype-anti-idiotype interactions in an autologous system (Andersson eta/., 1977; Cosenza et al., 1977; Nesterenko & Chernyakhovskaya, 1977; Owen et al., 1977; Urbain et al., 1977; Kraskina, 1979). The network theory (Jerne, 1974) assumes some other events that might regulate the functional activity of lymphocytes responding to autologous differentiation antigens. According to the plus-minus model (Hoffmann, 1975), idiotype-positive lymphocytes can be regulated by anti-idiotype (negative) cells. Consequently, the binding sites (paratopes) of the latter must have a structure identical with (or similar to) that of the autologous differentiation antigens which are recognized by idiotype-positive cells (Fig. 3). Again we are faced with a clear relationship between V-genes coding for the idiotypes of antigen-recognizing receptors of negative lymphocytes and the genes coding for structures to be recognized (autologous differentiation antigens). According to the present hypothesis, lymphocytes play an important role in somatic cell differentiation. But differentiation of tissues is known to
t
n
tl
FIG. 3. Regulatory effect of idiotype-anti-idiotype interactions on the activity of lymphocytes responsive to autologous differentiation antigens according to Hoffmann's plus-minus model. For designations see legends to Figs 1 and 2.
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v . G . NESTERENKO
Occur in utero, before the fetus has acquired an immunological system of its own. In my opinion, immune regulation of target cell differentiation is only possible in a mature organism with preformed organ and tissue systems (including the lymphoid system). In other words, autologous lymphocytes can regulate differentiation of cells only within "adult" systems that have traversed their genetically determined path of development. Such regulatory activity in utero would have interfered with the appearance of structures formed de novo during embryogenesis and would have been lethal for the fetus. Certainly, I do not deny the importance of immune surveillance for maintaining homeostasis and eliminating cells that have undergone mutation, been modified or destroyed by various agents. I only wish to draw attention to another function possibly performed by the immune system, the function of subtle regulation of autologous cell differentiation. Maybe this hypothesis will help to explain immune stimulation of tumor growth described by a number of authors (Prehn, 1971, 1972, 1976; Prehn & Lappe, 1971; Bonmassar et al., 1974; Jeejeebhoy, 1974), which cannot be accounted for by the concept of immune surveillance. Such stimulation might be caused either by a distorted response to differentiation antigens or by a normal response to specific tumor antigens mimicking the latter. I believe that the immune system has arisen during phylogeny primarily for recognition of self and only in this context has acquired its opposite function of recognizing non-self (see Table 1). The antigens of the major histocompatibility complex (MHC) are recognized just as any other surface differentiation antigens, and their special role in cell differentiation and MHC restriction of the recognition of foreign substances by T-lymphocytes might depend on the following circumstances: (1) presence of MHC components on all cells of the organism (including thymus and bone marrow cells) and, consequently, their involvement in lymphocyte selection during ontogeny (Jerne, 1971; Janeway, Wigzell & Binz, 1976); (2) their ability to influence in some way the presentation of foreign antigens on cell surface (Zinkernagel & Doherty, 1977; Benacerraf, 1980); (3) the existence of selected T-cells which recognize MHC antigens (but are not stimulated by them) via one of the two surface receptors (dual recognition theory) or via one binding site in a complex receptor (altered self recognition theory). Such restriction of T-cell recognition of foreign matter might be mediated also by other differentiation antigens endowed with similar properties (e.g. TL or Qa-2). Drawing a parallel with immune responses to foreign antigens, it might be suggested that the lymphocytes responding to autologous differentiation antigens comprise several subpopulations (suppressors, helpers, effectors
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TABLE 1
Presumed evolution of the ability to recognize self and non-self during phylogeny Useful for Stages of evolution I
II
III
Instances observed among metazoat
Response to
what is what is being recognizing recognized
Cells of sponges (metazoa characterized by the lowest level of organization) have a capacity for specific inter-individual reaggregation within the same species. Instances of recognition of self in mammals are cited in the beginning of the present paper (see items 2, 3, 4 and 6) Hybrids F 1 of Tonicata reject allogeneic but not semisyngeneic cells. Here it might be possible to draw a parallel with allogeneic inhibition (syngeneic preference or hybrid resistance) in mammals Response to non-self has been documented in Coelenterata. Its various manifestations have been described in mammals
Self
+
Absence of self
+
Non-self
+
+
t Hildemann & Reddy, 1973; Hildemann, 1974; Cooper, 1976. etc.). H o w e v e r , m o r e c o m p l e x m o d e l s of i m m u n e r e g u l a t i o n of cell differe n t i a t i o n c a n n o t be p r o p o s e d at p r e s e n t d u e to lack of e x p e r i m e n t a l evidence. T h e m e c h a n i s m s u n d e r l y i n g the r e g u l a t i o n of t a r g e t cell differentia t i o n by l y m p h o c y t e s are u n k n o w n . P r o b a b l y t h e y are m o r e or less similar to the m e c h a n i s m s t h a t e n s u r e i n t e r a c t i o n b e t w e e n the different s u b p o p u l a t i o n s of l y m p h o c y t e s a n d t h e e x p r e s s i o n of t h e i r g e n e t i c p r o g r a m s d u r i n g i m m u n e r e s p o n s e to f o r e i g n antigens. The author is indebted to Professor L. N. Fontalin for a fruitful discussion of this paper. REFERENCES ANDERSSON, A. D. & ANDERSSON, N. D. (1976). Immunology 31, 731. ANDERSSON, L. C., WIGHT, E., AGUET, M., ANDERSSON, R., BINZ, H. & WIGZELL, H. (1977). J. exp. Med. 146, 1124. ARDRY, R., COURTIN, A. & THU, N. T. (1966). Ann. pharmac. #an~. 24, 717. AUER, J., TOMAS, T. B. & MILGROM, F. (1974). Cell. Immunol. 10, 404. AUFIERO, C., RENDA, G., FRANCISCIS,P. & SCARANO, E. (1964). Boll. Soc. ital. biol. sperim. 40, 1713. AVERCHENKO, V. I. & MOVSHEV, B. E. (1969). Bull. exp. Biol. Med. (Moscow). 5, 83.
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GOODMAN, J. W., BASFORD,N. L. & SHINPOCK,S. G. (1975). Transplantation Today 3, 809. GOZES, Y., UMmL, T., MESHORER, A. & TRAININ, N. (1978). J. lmmunol, 121, 2199. HAMMARSTROM, L., SMITH, E., PRIMI, D. & MOLLER, G. (1976). Nature 263, 60. H.~.MMERLING, G. J., BLACK, S. J., BEREK, C., EICHMANN,K. & RAJEWSKY,K. (1976). J. exp. Med. 143, 861. HERZENBERG, L. A., OKUMURA, K. & CANTOR, H. (1976). J. exp. Med. 144, 330. HIERNAUX, J. (1977). Immunochemistry 14, 733. HILDEMANN, W. H. (1974). Nature 250, 116. HILDEMANN, W. H. & REDDY, A. L. (1973). Fedn Proc. 32, 2188. HOFFMANN, G. W. (1975). Eur. J. Immunol. 5, 638. HOWE, M. L. (1973). J. Immunol. 110, 1090. JANEWAY, C. A., WlGZELL, H. & BINZ, H. (1976). Scand. J. lmmunoL 5, 993. JEEJEEBHOY. H. F. (1974). Int. J. Cancer 13, 665. JERNE, N. K. (1971). Eur. J. Immunol. 1, 1. JERNE, N. K. (1974). Ann. Inst. Pasteur 125C, 373. KAPLAN, M. H. & MEYESERIAN, M. (1962). Lancet 1, 706. KEMLER, R., BABINET, C., EISEN, H. & JACOB, F. (1977). Proc. natn. Acad. Sci. U.S.A. 74, 4449. KIMURA, m. K. & WIGZELL, H. (1977). Contemp. Topics Mol. lmmunol. 6, 209. KITAMURA, Y., KAWATA, T. & KANAMARU, A. (1972). Transplantation 14, 568. KOLPASCHIKOVA, E. F. (1978). Bull exp. Biol. Med. (Moscow) 4, 410. KOHLER, H., RICHARDSON, B. C. & SMYK, S. (1978). J. lmmunol. 120, 233. KRASKINA, N. A. (1979). Problems Microbiol. Immunol. Infect. Dis. (Moscow) 22, 3. KUNTZ, M., INNES, J. B. & WEKSLER, M. E. (1976). Z exp. Med. 143, 1042. LYAMPERT, I. M. & DANILOVA, T. K. (1975). Progr. Allergy 18, 423. MAINO, V. C., HAYMAN, M. J. & CRUMPTON, M. J. (1975). Biochem. J. 146, 247. MECHNIKOFF, I. I. (t901). Russ. Arkhiv Pathol. 11, 101. MICHAELSON, J., FLAHERTY, L., VITETTA, E. & POULIK, M. D. (1977). J. exp. Med. 145, 1066. MILLER, R. A. & KAPLAN, H. S. (1978). Z lmmunol, 121, 2165. NESTERENKO,V. G. & CHERNYAKHOVSKAYA,I. U. (1977). Bull. exp. Biol. Med. (Moscow) 12, 693. NESTERENKO, V. G. & GRUNER, S. (1980). Bull exp. Biol. Med. (Moscow) 6, 708. NESTERENKO, V. G. & KOVALCHUK,I. V. (1976). Bull exp. Biol. Med. (Moscow) 7, 836. NESTERENKO, V. G., KRASKINA,N. A., RUBAKOVA, E. I. & GRUNER, Sh. (1982). Celt. lmmunol, 69, 215. NESTERENKO, V. G., NOVIKOVA, T. K. & FONTALIN, L. N. (1980). In: Advances in Comparative Leukemia Research 1979 (Lapin, B . & Yohm, E. F. eds). Moscow: Acad. Med. Sci. USSR/IET. NIEDERHUBER, J. E., BRI'I-FON,S. & BERGUIST, R. J. (1972). Z lmmunol. 109, 366. OPELZ, G., KIUCHI, M., TAKASUG1,M. & TERASAKI, P. J. (1975). J. exp. Med. 142, 132. OWEN, F. L., Ju, S. T. & NISONOFF, A. (t977). Z exp. Med. 145, 1559. PECK, A. B., WIGZELL, H., JANEWAY, C. & ANDERSSON, L. C. (1977). Immunol, ReD. 35, 146. PILLEMER, E. & WEISSMAN, I. L. (1981). Z exp. Med. 153, 1068. PLXSKIN, M. E. & PREHN, R. T. (1975). J. Reticuloendothel. Soc. 17, 290. PONZIO, N. M., FINK, J. H. & BATrlSTO, J. R. (1975). 2. Immunol. 144, 971. POUPLARD, A., BOTTAZZO, O. F., DONIACH, D. & RIOTr, L. M. (1976). Nature 261, 142. PREHN, R. T. (1971). J. Reticuloendothel. Soc. 10, 1. PREHN, R. T. (1972). Science 176, 170. PREHN, R. T. (1976). J. ham. Cancerlnst. 56, 833. PREHN, R. T. & LAPPE, M. A. (1971). Transplant. Rev. 7, 26. RADOSEVIC-STASIC,B. & RUKAVINA, D. (1979). Periodicum Biologorum 81, 151. RAFF, M. C. (1971). Transplant. Rev. 6, 52. RAMSEIER, H. (1979). Expl cell, Biol. 47, 107.
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RICHTER, P. H. (1975). Eur. J. lmmunol. 5, 350. RODIONOV, G. A. & KOROL, C. A. (1963). Mechanisms of Old Age. Moscow: Meditsina. RODKEY, L. S. (1976). J. Immunol. 117, 986. ROWLEY, D. A., FITCH, F. W., STUART, F. P., KOHLER, H. & COSENZA, H. (1973). Science 181, 1133. SAWADA, S., PILLERISETTY, R. J., MICHALSKY, J. P., PALMER, D. W. & TATAL, N. (1977). J. lmmunol. 119, 355. SHEARER, W. T., PHILPOT'r, G. W. & PARKER, C. W. (1975). Cell Immunol. 17, 447. SHIRAI, T., YOSHIKU, T. & MELLORS, R. C. (1972). J. lmmunol. 109, 32. SIDMAN,C. L. & UNANUE, E. R. (1978). Proc. natn. Acad. Sci. U.S.A. 75, 2401. STEINMAN,R. A. & WITMER,M. D. (I978). Proc. natn. Acad. Sci. U.S.A. 75, 5132. STOBO, J. D. & LOEHNEU, C. P. (1976). Mayo Clin. Proc. 51, 479. SULLIVAN, R. A., BERKE, G. & AMOS, D. B. (1973). Transplantation 16, 388. SVET-MOLDAVSKY, G. J., SCHVASABAYA, E. K. & ZINZAR, S. N. (1974). Reports Acad. Sci. U.S.S.R. 218, 246. TAKAHASH1, T., OLD, L. J. & BOYSE, E. A. (1970). J. exp. Med. 131, 1325. TATAL, N. (1976). Transplant. Rev. 31, 240. THOMAS, D. B. (1974). Eur. J. lmmunol. 4, 819. THOMAS, D. B. & PHILLIPS, B. (1973). Clin. exp. lmmunol. 14, 91. TRENKNER, E. & SARKAR, S. (1977). J. Supramol. Str. 6, 465. URBAIN, J., WIKLER, M., FRANSSEN, J, D. & COLLIGNON, C. (1977). Proc. hath. Acad. Sci. U.S.A. 74, 5126. VITETTA, E. S., ARTZT, K., BENNETT, D., BOYSE, E. A. & JACOB, F. (1975). Proc. natn. Acad. Sci. U.S.A. 72, 3215. VON BOEHMER, H. & BYRD, W. J. (1972). Nature 235, 50. VON BOEHMER, H., HAAS, W. & JERNE, N. (1978). Proc. ham. Acad. Sci. U.S.A. 75, 2439. VVAZOV, O. E. & BARABANOV, V. M. (1973). The Bases o/lmmunoembryology. Moscow: Meditsina. WALKER, D. G. (1975). Science 190, 784. WARNATZ,H., SCHEIFFARTH,F., WOLF, F. & SCHMIDT,H. J. (1967). J. lmmunol. 98, 406. WEBER, W. T. (1977). In: Regulatory Mechanisms in Lymphocyte Activation (Lucas, D. O. ed.) New York: Academic Press. WEIGLE, W. O. (1975). J. Reticuloendothel. Soc. 17, 179. WEKSLER, M. E. & KOZAK, R. (1977). J. exp. Med. 146, 1833. WINCHESTER, R. J., ROSS, C. D., JAROWSKI, C. J., WANG, C. Y., HALPER, J. & BROXMEYER, H. E. (1977). Proc. natn. Acad. Sci. U.S.A. 74, 4012. WOODLAND,R. & CANTOR, H. (1978). Eur. J. lmmunol. 8, 600. WOODRUFF, M. F. A., REID, B. & JAMES, K. (1967). Nature 215, 591. YAMASHITA, U., TAKAMI, Z., HAMAOKA, Z. • KITAGAWA, M. (1976). Cell. lmmunol. 25, 15. ZINKERNAGEL, R. M., COLLAHAN, G. N., ALTHAGE, A., COOPER, S., KLEIN, P. A. & KLEIN, J. (1978). J. exp. Med. 147, 882. Z1NKERNAGEL, R. M. & DOHERTY, P. C. (1977). Contemp. Topics Immunobiol. 7, 179.
A Concept of Immune Regulation of Somatic Cell Differentiation V. G. NESTERENKO
Laboratory of Immunological Tolerance, Gamaleya Institute of Epidemiology and Microbiology, U.S.S.R. Academy of Medical Science, Gamaleya St. 18, Moscow 123098, U.S.S.R. (Received 8 November 1982, and in revised form 11 October 1983) On the basis of several lines of experimental evidence a hypothesis is advanced on autoimmune regulation of somatic cell differentiation in an immunologicallymature organism ("self-anti-self"hypothesis of differentiation). There are supposed to be clones of lymphocytes interacting via their antigen-recognizing receptors with autologous differentiation antigens on various target cells. This interaction would modify the genetically determined rate of cell differentiation. Some implications of the hypothesis are discussed in relation to immunological memory, tolerance etc. In particular, the new concept might imply similarity (or identity) of the genes coding for autologous differentiation antigens and those responsible for the idiotypes of antigen-recognizing lymphocyte receptors. The key function of adult lymphoid tissue is understood to be generation of immune responses to various antigens (antigens of cell mutants, microbial and viral antigens etc.). These responses maintain homeostasis and stability of the antigenic structure of the internal milieu (Burnet, 1959, 1969; Brondz & Rokhlin, 1978). An immune response to unmodified autologous antigens is usually considered pathological (Burnet, 1959, 1969; Weigle, 1975; Stobo & Loehneu, 1976; Fontalin & Pevnitsky, 1978). Yet there are observations indicating that immune responses to some autoantigens are not abnormal but may be regarded as an essential step in lymphocyte differentiation (Jerne, 1971; Zinkernagel & Doherty, 1977; Zinkernagel et al., 1978; Benacerraf, 1980). Here a hypothesis is advanced which proposes that the immune response to a number of autoantigens supports differentiation not only of lymphocytes but also of other target cells. The term "differentiation antigen" is used below to designate surface antigens formed on cells at a certain stage of development and disappearing during further differentiation. The present hypothesis assumes the existence of lymphocytes capable of interacting via their antigen-recognizing receptors with differentiation anti0022-5193/84/070443 + 14 $03.00/0
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gens of various autologous somatic cells. Such interaction modifies the genetically determined rate of cell differentiation. No tolerance is acquired to autologous differentiation antigens, since their concentrations are usually variable and low (too low also for induction of tolerance based on clone deletion or suppression), and only sometimes exceed a certain threshold which provokes the response of lymphocytes. Let us suppose (Fig. 1) that a clone of anti-A1 lymphocytes interacts in vivo with somatic cells carrying differentiation antigen A1. As a result, the transition of cells from functional state A I to state A2 (marked by differentiation antigen A2) is either accelerated or delayed. Subsequently the receptors of an anti-A2 lymphocyte clone will react specifically with differentiation antigen A2 modulating the speed of transition to functional state A3 (marked by differentiation antigen A3) and so on. In the light of this hypothesis, antigen-recognizing receptors (or antibodies) may be considered a kind of differentiation "hormones". Further on, for the sake of simplicity, only those situations will be discussed when transition to another functional state is accelerated by the contact between antigen-recognizing receptors and differentiation antigens. Naturally, a delayed transition can also occur. My hypothesis is based on eight lines of evidence reported in the relevant literature: (1) changes in the spectrum of surface antigens accompanying cell differentiation; (2) existence of lymphocytes potentially capable of responding to autologous antigens; (3) recognition of autologous antigens of the major histocompatibility complex (MHC) by T-lymphocyte receptors; (4) existence of an autologous idiotype-anti-idiotype network; (5) regulation of the differentiation of somatic cells by antibodies to their surface antigens; (6) discovery of morphogenetic lymphocyte activity; (7) effect of thymectomy on the rate of reparative events; (8) antigenic and/or structural homology between Ig and some cell surface antigens and regulatory molecules. Below, all this evidence will be discussed in detail. (1) Various cell transformations are known to be accompanied by the appearance of new surface antigens. Thus, during proliferation, cells exhibit antigens which cannot be detected on resting cells (Thomas & Phillips, 1973; Thomas, 1974; Bluming et al., 1975; Feeney & H/immerling, 1976; Nesterenko & Kovalchuk, 1976; Nesterenko & Gruner, 1980; Nesterenko, Novikova & Fontalin, 1980). In early phases of differentiation the antigenic structure of granulocytes differs from that of mature cells (Winchester et al., 1977). T- and B-tymphocytes acquire dissimilar and specific antigens as they evolve from the stem cell (Raft, 1971; Niederhuber, Britton & Berguist, 1972; Cantor & Boyse, 1977). Effector cells involved in immune responses possess antigens which are absent on less differentiated lym-
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phocytes (Takahashi, Old & Boyse, 1970; Sullivan, Berke & Amos, 1973; Kimura & Wigzell, 1977; Nesterenko et al., 1980). When thymocytes differentiate into T-lymphocytes, F9 antigen is replaced on their surface by H-2 antigens, and TL antigens are replaced by Qa-2 antigens (Vitetta et al., 1975; Michaelson etaL, 1977). This list of examples is far from complete, but it is sufficient to demonstrate the variability of surface antigens and their dependence on cell differentiation stages. (2) The autologous system has been shown to contain lymphocytes with a potential capacity of responding to a number of antigens which are usually in contact with them in vivo: immunoglobulins (Ig) (Herzenberg, Okumura & Cantor, 1976; Rodkey, 1976; Cosenza, Augustin & Julius, 1977; Owen, Ju & Nisonoff, 1977; K6hler, Richardson & Smyk, 1978), DNA and RNA (Tatal, 1976; Sawada et al., 1977), antigens on erythrocytes (Cox & Keast, 1973; Gleichmann & Gleichmann, 1976; HammarstrSm et al., 1976; Yamashita et aL, 1976), on thymus cells and T-lymphocytes (Shirai, Yoshiku & Mellors, 1972; Bretscher, 1973; Fugi & Milgrom, 1973; Auer, Tomas & Milgrom, 1974; Zinkernagel et al., 1978), on B-lymphocytes (Opelz et al., 1975; Kuntz, Innes & Weksler, 1976; Weksler & Kozak, 1977). There are also lymphocytes capable of responding to antigens of the myocardium (Kaplan & Meyeserian, 1962; Lyampert & Danilova, 1975), those of the hepatic (Eddleston & Williams, 1974), renal (Vyazov & Barabanov, 1973; Borel, Lewis & Stollar, 1973), splenic tissues (Howe, 1973), lymph node endothelium (Andersson & Andersson, 1976), antigens on macrophages and reticulocytes (Steinman & Witmer, 1978) and other cell-associated antigens (von Boehmer & Byrd, 1972; Cohen & Wekerle, 1973; Ponzio, Fink & Battisto, 1975; Ching, Marbrook & Walker, 1977; Peck et al., 1977; Gozes et al., 1978; Miller & Kaplan, 1978). (3) T-lymphocytes have been found to carry receptors recognizing the autologous antigens of MHC (Zinkernagel & Doherty, 1977; von Boehmer, Haas & Jerne, 1978; Benacerraf, 1980). (4) The immune response to idiotypic antigenic determinants of autologous Ig or cellular antigen-recognizing receptors is supposed to be a normal event regulating the development of a given idiotype and, consequently, the functioning of idiotype-positive lymphocytes (Rowley et al., 1973; Jerne, 1974; Hoffmann, 1975; Richter, 1975; Binz & Wigzell, 1977; Hiernaux, 1977; Nesterenko & Chernyakhovskaya, 1977; Woodland & Cantor, 1978; Kraskina, 1979; Nesterenko et al., 1982). (5) Somatic cell differentiation can be regulated in various animal models by antibodies produced experimentally to components of the cell surface. Antibodies are known to mediate killing of target cells by complement. It has also been established that they can block cell differentiation at a certain
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stage. Thus, Fab fragments of rabbit antibodies to F9 antigen, when added to mouse embryo cultures 32 to 36 hours after their initiation, did not influence cell cleavage but prevented the formation of a compact morula and blastocyst. This effect was reversible: the blastocyst could be formed if incubation was continued after removal of the antibodies. Moreover, washed embryonal cells which had been transferred to pseudopregnant females gave rise to normal progeny. When the stage of the blastocyst was attained, the cells lost sensitivity to the blocking action of the antibodies (Kemler et al., 1977). Trenkner & Sarkar (1977) showed that addition of antibodies against polysaccharide antigens to cultures of murine cerebellar cells suppressed reversibly their differentiation. If antibodies were washed off within one or two days, differentiation was resumed. On the other hand, a number of investigators reported a stimulating effect of antibodies on proliferation and morphogenesis. As early as 1901, Mechnikoff found that small amounts of cytotoxic sera, in contrast to large doses, increased the functional and proliferative activities of the target organ. Experiments done in vivo and in vitro demonstrated a marked growth-promoting effect of anti-reticular serum on tissues of mesenchymal origin (Bogomolets, 1956). Rodionov & Korol (1963) described enhancement of proliferative processes in the livers of animals injected with anti-hepatic serum. Ardry, Courtin & Thu (1966) showed that antisera against osseous and cartilaginous tissues stimulated repair of bone fractures. Both anti-lymphocyte sera (Woodruff, Reid & James, 1967; Falcott, Oriol & Iscaki, 1972; Weber, 1977) and anti-Ig antibodies (Maino, Hayman & Crumpton, 1975; Bell & Wigzell, 1977; Sidman & Unanue, 1978) induced proliferation of lymphocytes. Several studies revealed a stimulating action of anti-idiotype antibodies on idiotype-positive lymphocytes (Eichmann & Rajewsky, 1975; H~immerling et al., 1976; Frischknecht, Binz & Wigzelt, 1978; Binz, Frischknecht & Wigzell, 1979; Ramseier, 1979). Shearer, Philpott & Parker (1975) observed enhanced proliferation of L-cells after treatment with a small amount of specific antibodies. (6) There are reports describing morphogenetic activity of lymphocytes, i.e. their capacity to influence differentiation of autologous (or syngeneic) somatic cells. A modulating effect on differentiation of syngeneic hemopoietic stem cells is a well-documented property of T-lymphocytes (Golovistikov, Petrov & Khaitov, 1970; Kitamura, Kawata & Kanamaru, 1972; Goodman, Basford & Shinpock, 1975). In many experiments the functional state of non-lymphoid somatic cells of a donor animal could be transferred with its lymphocytes to a syngeneic recipient. Thus, viable spleen lymphocytes taken from partially hepatectomized mice induced high proliferative activity of parenchymatous and reticulo-endothelial cells in the livers
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of intact animals. The mitotic index in salivary glands and renal tubular epithelium of the recipients remained unaltered and was slightly increased in renal connective tissue (to a much lesser extent than in liver cells). On the other hand, transfer of lymphoid cells isolated from murine spleens after unilateral nephrectomy led to an insignificant increase in the mitotic index of liver reticulo-endothelial cells but markedly augmented that of renal tubular epithelium (Babaeva, Kraskina & Liozner, 1969a, b). Subsequently it came out that the capacity of transmitting the stimulus to proliferation resided in T-lymphocytes (Babaeva, Kraskina & Udina, 1980). Similar results were obtained by Fox & Wahman (1968), Pilskin & Prehn (1975), Radosevic-Stasic & Rukavina (1979). Using lymphocytes from affected donors, Warnatz et aL, (1967) and Kolpaschikova (1978) reproduced in normal syngeneic recipients certain changes typical for hepatitis caused by carbon tetrachloride or a homogenate of allogeneic liver. SvetMoldavsky, Schvasabaya & Zinzar (1974) observed cardiomegaly in mice injected with lymphoid cells from syngeneic donors whose hearts had hypertrophied due to experimental aortic stenosis. A rise in blood sugar level was recorded in recipients of T-lymphocytes from syngeneic mice with streptozotocin-induced diabetes (Buschard & Rygaard, 1978). Spleen cells from mice with osteopetrosis could provoke the disease in intact syngeneic animals (Walker, 1975). In Dolgushin's experiments (1978) transfer of lymphoid cells from syngeneic donors stimulated the healing of skin burns in irradiated recipients. This effect was especially pronounced if the donors also had burns. Interestingly, Babaeva, Nesterenko & Udina (1982) showed that lymphocytes from mice twice subjected to partial hepatectomy had a greater ability to enhance proliferation of liver cells in intact recipients as compared to those from the survivors of a single operation. This observation calls to mind the well-known phenomenon of the development of immunological memory during the primary response to a foreign antigen. (7) According to a number of authors, thymectomy changes the rate of repair after experimental injuries. Thus, Averchenko & Movshev (1969) studied bone regeneration in rats thymectomized upon reaching maturity. The incorporation of radioactive calcium into regenerating (and normal) bone tissue was considerably lowered in these animals, especially" if regeneration took place after repeated injury. Several investigators (Davies et al., 1964; Dukor & Miller, 1965; Forabosco & Toni, 1969; Babaeva, 1972) came to the conclusion that thymectomy inhibited proliferative processes in the regenerating liver. An opposite opinion was expressed by Aufiero et al. (1964), who insisted that regeneration of the liver was more complete in rats subjected to adult thymectomy than in control animals. It would be difficult to propose an
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explanation of such discrepancies. Of paramount importance is the fact that thymectomy alters the rate of organ and tissue repair, and as for the direction of the changes, it might depend on the particular experimental conditions. These data possibly suggest involvement of the immune T-system in reparative events. (8) According to Coligan et al. (1981), H-2 antigens and Ig have homologous amino acid sequences. Homology in the structure of Ig and that of Thy-1 antigen has been detected by Cohen et al. (1981). Moreover, Thy-1 antigen has been shown to share antigenic determinants with the V region of the light chain in Ig (Pillemer & Weissman, 1981). Hormoneproducing ceils of the anterior pituitary have been found to carry surface Ig (Pouplard etal., 1976; Boyd, Peters & Morris, 1978), which are supposed to influence their functional activity. Moreover, common antigenic characteristics have been detected in Ig and several pituitary hormones. Thus, precipitation lines of identity could be observed between the luteinizing, follicle-stimulating, thyrotrophic and gonadotrophic hormones, and IgG antigenic determinants, as well as between the gonadotrophic and thyrotrophic hormones, and IgA determinants. The significance of these observations in relation to my hypothesis will be clarified below. The model of target cell differentiation under the action of autologous lymphocytes, which is outlined in Fig. 1, implies the occurrence of the following events. (a) Lymphocytes from a donor whose somatic cells are in a certain functional state can transmit this state to syngeneic recipients. Thus, transfer of anti-Ak lymphocytes would accelerate the transition of non-lymphoid somatic cells from state Ak to Ak÷~.
!
t anti-A~
2
T onti-Az
3
T anli- A3
~
T anti- Ak
n-1
n
1 anti- An- 1
FIG. 1. Immune regulation of target cell differentiation. A~, A2, Aa, Ak, A._1, An= differentiation antigens of target cells in states A1, A2, m 3, Ak, An- 1 and A, respectively. ~, direction of the interaction of lymphocyteswith autologous differentiation antigens. direction of target cell differentiation.
SELF-ANTI-SELF
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HYPOTHESIS
(b) Autologous differentiation antigens can elicit a secondary immune response. Consequently, state Ak÷l would develop more rapidly in syngeneic recipients if they receive lymphocytes from a donor with state Ak created repeatedly and not for the first time. (c) Immunological non-responsiveness to differentiation antigens, for instance, to antigen Ak, can be induced artificially. In such a case transition from state Ak tO Ak+~ would be delayed. Tolerance of a suppressive type could be transferred with donor lymphocytes to an intact recipient. If tolerance in a donor animal results from anti-Ak clone deletion, its lymphocytes would fail to influence the recipient's somatic cells exhibiting state
Ak. A prerequisite for interaction of anti-Ak lymphocytes with differentiation antigen Ak (as for immune responses of all other types) is probably the presence of the antigen in a certain threshold concentration. The number of target cells carrying antigen Ak decreases when they are stimulated to attain the functional state associated with antigen Ak+~.However, the model shown in Fig. 1 does not provide for any direct immune interactions that would alter the level of antigen Ak with a rise in antigen Ak÷~, i.e. it has no feedback. Another version of this model comprising a feedback system is depicted in Fig. 2. Let us suppose that differentiation antigen Ak-1 and
t
t
l
onti-,~ I
onti-Zt 2
anti-A 3
ctnti-,~k. 1
t
t
anti-~ k
anti-A n
FIG. 2. A modelof immuneregulationof target cell differentiationcomprisinga feedback system. Shaded structures are idiotypicantigenic determinants. For other designationssee legend to Fig. 1. the idiotype of anti-Ak lymphocyte receptors have identical (or similar) determinants. Therefore the antigen-recognizing receptors of anti-Ak-1 lymphocytes will interact with the latter idiotype, as well as with antigen Ak-1. In such a case the transition from state Ak-~ tO Ak brought about by the interaction of antigen Ak-~ with anti-Ak_~ lymphocytes will not only
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V. G. N E S T E R E N K O
augment the number of cells carrying antigen Ak, but also be accompanied by a response of anti-Ak-2 lymphocytes to the high level of anti-Ak-~ idiotype. The resulting rise in the level of anti-Ak-2 idiotype will probably enhance its interaction with antigen Ak-2 and abrogate (or weaken) the response of anti-Ak-~ idiotype to antigen Ak-1. Consequently, the cells that have remained in state Ak-2 would attain state Ak-i m o r e rapidly. According to the model presented in Fig. 2, the immune response of anti-Ak lymphocytes to antigen Ak will suppress anti-Ak+l lymphocytes (since anti-Ak lymphocytes interact with anti-Ak÷1 idiotype) and stimulate anti-Ak_l lymphocytes (which respond to anti-Ak idiotype). This will accelerate the transition of target cells from state Ak t o Ak+l and from Ak-1 tO Ak, and delay the transition from Ak+1 t o Ak+2. Induction of immune non-responsiveness to antigen Ak will result in opposite changes: transition from state Ak t o Ak+t and from Ak-! to Ak will be delayed, while transition from Ak+l t o Ak+2 will proceed faster. If the model of Fig. 2 is valid, anti-differentiation antibodies would be active not only against their differentiation antigen, but also against the idiotype of the lymphocytes recognizing the next antigen in the sequence of target cell differentiation, while anti-idiotype antibodies would interact with the first antigen. Thus, lymphocytes from partially hepatectomized mice would fail to transmit high mitotic activity to the recipient's hepatic cells after treatment in vitro with antibodies directed against the antigens of regenerating liver (anti-differentiation antibodies) in the presence of complement. On the other hand, absorption of anti-idiotype serum with antigens of regenerating liver would eliminate antibodies directed against the idiotype of the donor lymphocytes. It should be noted that model 2 implies an intimate relationship between the genes coding for the idiotypes of lymphocyte receptors which recognize autologous differentiation antigens, and the genes responsible for the synthesis of the latter. They constitute a single group, but not two distinct classes. Each gene of the group can code both for the recognizing structure and for what is being recognized. It may be assumed that only this strictly limited set of genes is subject to hereditary transmission, while all the diversity of antigen-recognizing receptors is generated during ontogeny by mutations, recombinations or similar events in V-genes of lymphoid cells proliferating under the influence of autologous differentiation antigens. Direct experiments which would validate model 2 have yet to be designed. However, there is some preliminary evidence that provides credence for this model: (a) homology of the structure of H-2 antigens and that of Ig (Coligan et al., 1981); (b) antigenic and structural similarities between Ig and Thy- 1 antigens (Cohen et al., 1981; Pillemer & Weissman, 1981); (c)
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HYPOTHESIS
the common antigenic characteristics found by Pouplard el aL (1976) and Boyd et al. (1978) in Ig and several hormones (which could act as differentiation antigens on the surface of hormone-producing cells), and (d) abundant data about the regulatory role of idiotype-anti-idiotype interactions in an autologous system (Andersson eta/., 1977; Cosenza et al., 1977; Nesterenko & Chernyakhovskaya, 1977; Owen et al., 1977; Urbain et al., 1977; Kraskina, 1979). The network theory (Jerne, 1974) assumes some other events that might regulate the functional activity of lymphocytes responding to autologous differentiation antigens. According to the plus-minus model (Hoffmann, 1975), idiotype-positive lymphocytes can be regulated by anti-idiotype (negative) cells. Consequently, the binding sites (paratopes) of the latter must have a structure identical with (or similar to) that of the autologous differentiation antigens which are recognized by idiotype-positive cells (Fig. 3). Again we are faced with a clear relationship between V-genes coding for the idiotypes of antigen-recognizing receptors of negative lymphocytes and the genes coding for structures to be recognized (autologous differentiation antigens). According to the present hypothesis, lymphocytes play an important role in somatic cell differentiation. But differentiation of tissues is known to
t
n
tl
FIG. 3. Regulatory effect of idiotype-anti-idiotype interactions on the activity of lymphocytes responsive to autologous differentiation antigens according to Hoffmann's plus-minus model. For designations see legends to Figs 1 and 2.
452
v . G . NESTERENKO
Occur in utero, before the fetus has acquired an immunological system of its own. In my opinion, immune regulation of target cell differentiation is only possible in a mature organism with preformed organ and tissue systems (including the lymphoid system). In other words, autologous lymphocytes can regulate differentiation of cells only within "adult" systems that have traversed their genetically determined path of development. Such regulatory activity in utero would have interfered with the appearance of structures formed de novo during embryogenesis and would have been lethal for the fetus. Certainly, I do not deny the importance of immune surveillance for maintaining homeostasis and eliminating cells that have undergone mutation, been modified or destroyed by various agents. I only wish to draw attention to another function possibly performed by the immune system, the function of subtle regulation of autologous cell differentiation. Maybe this hypothesis will help to explain immune stimulation of tumor growth described by a number of authors (Prehn, 1971, 1972, 1976; Prehn & Lappe, 1971; Bonmassar et al., 1974; Jeejeebhoy, 1974), which cannot be accounted for by the concept of immune surveillance. Such stimulation might be caused either by a distorted response to differentiation antigens or by a normal response to specific tumor antigens mimicking the latter. I believe that the immune system has arisen during phylogeny primarily for recognition of self and only in this context has acquired its opposite function of recognizing non-self (see Table 1). The antigens of the major histocompatibility complex (MHC) are recognized just as any other surface differentiation antigens, and their special role in cell differentiation and MHC restriction of the recognition of foreign substances by T-lymphocytes might depend on the following circumstances: (1) presence of MHC components on all cells of the organism (including thymus and bone marrow cells) and, consequently, their involvement in lymphocyte selection during ontogeny (Jerne, 1971; Janeway, Wigzell & Binz, 1976); (2) their ability to influence in some way the presentation of foreign antigens on cell surface (Zinkernagel & Doherty, 1977; Benacerraf, 1980); (3) the existence of selected T-cells which recognize MHC antigens (but are not stimulated by them) via one of the two surface receptors (dual recognition theory) or via one binding site in a complex receptor (altered self recognition theory). Such restriction of T-cell recognition of foreign matter might be mediated also by other differentiation antigens endowed with similar properties (e.g. TL or Qa-2). Drawing a parallel with immune responses to foreign antigens, it might be suggested that the lymphocytes responding to autologous differentiation antigens comprise several subpopulations (suppressors, helpers, effectors
SELF-ANTI-SELF HYPOTHESIS
453
TABLE 1
Presumed evolution of the ability to recognize self and non-self during phylogeny Useful for Stages of evolution I
II
III
Instances observed among metazoat
Response to
what is what is being recognizing recognized
Cells of sponges (metazoa characterized by the lowest level of organization) have a capacity for specific inter-individual reaggregation within the same species. Instances of recognition of self in mammals are cited in the beginning of the present paper (see items 2, 3, 4 and 6) Hybrids F 1 of Tonicata reject allogeneic but not semisyngeneic cells. Here it might be possible to draw a parallel with allogeneic inhibition (syngeneic preference or hybrid resistance) in mammals Response to non-self has been documented in Coelenterata. Its various manifestations have been described in mammals
Self
+
Absence of self
+
Non-self
+
+
t Hildemann & Reddy, 1973; Hildemann, 1974; Cooper, 1976. etc.). H o w e v e r , m o r e c o m p l e x m o d e l s of i m m u n e r e g u l a t i o n of cell differe n t i a t i o n c a n n o t be p r o p o s e d at p r e s e n t d u e to lack of e x p e r i m e n t a l evidence. T h e m e c h a n i s m s u n d e r l y i n g the r e g u l a t i o n of t a r g e t cell differentia t i o n by l y m p h o c y t e s are u n k n o w n . P r o b a b l y t h e y are m o r e or less similar to the m e c h a n i s m s t h a t e n s u r e i n t e r a c t i o n b e t w e e n the different s u b p o p u l a t i o n s of l y m p h o c y t e s a n d t h e e x p r e s s i o n of t h e i r g e n e t i c p r o g r a m s d u r i n g i m m u n e r e s p o n s e to f o r e i g n antigens. The author is indebted to Professor L. N. Fontalin for a fruitful discussion of this paper. REFERENCES ANDERSSON, A. D. & ANDERSSON, N. D. (1976). Immunology 31, 731. ANDERSSON, L. C., WIGHT, E., AGUET, M., ANDERSSON, R., BINZ, H. & WIGZELL, H. (1977). J. exp. Med. 146, 1124. ARDRY, R., COURTIN, A. & THU, N. T. (1966). Ann. pharmac. #an~. 24, 717. AUER, J., TOMAS, T. B. & MILGROM, F. (1974). Cell. Immunol. 10, 404. AUFIERO, C., RENDA, G., FRANCISCIS,P. & SCARANO, E. (1964). Boll. Soc. ital. biol. sperim. 40, 1713. AVERCHENKO, V. I. & MOVSHEV, B. E. (1969). Bull. exp. Biol. Med. (Moscow). 5, 83.
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