J. theor. Biol. (1976) 57, 121-129

Mechanism for Regulation of Immune Responses~ JAN JAROSZEWSKI,~ AFTAB AI-IMED AND KENNETH W. SELL

Department of Clinical and Experimental Immunology, Naval Medical Research Institute, Bethesda, Maryland 20014, U.S.A. (Received 1 November 1974, and in revised form 1 April 1975) Several mechanisms for the control of immune responses have been postulated (Bretscher & Cohn, 1968; Cohen, 1970; Bretscher, 1972; Jerne, 1974; Marchalonis, Morris & Harris, 1974). During the course of several lines of investigation carried out in our laboratory, evidence has been accumulating that would suggest a possible mechanism for the regulation of immune responses. We suggest that a new antigen is produced on the surface of lymphocytes following antigenic recognition and induction of blast transformation; and that these new surface "blast" antigens may induce the immune reaction of another lymphocyte. If such new antigens are specific for the original antigenic stimulus, the immune response against the antigen-specific blast cells might provide the way of controlling immune responses. This reaction might also produce the stimulus necessary to stimulate B lymphocytes to produce antibody (T-helper function).

1. Introduction

Several lines of evidence i.ndicate that, similar to other mammalian cells, the lymphocyte surface undergoes prominent changes upon transition of the cell from resting state to proliferation. Membrane antigens specific for B or T lymphoblasts, but absent from resting lymphocytes, were described (Thomas & Phillips, 1973). Rabbit antisera against PHA-induced blast cells have very weak mitogenic potency (Warnatz, Scheiffarth & Hiltl, 1972) in contrast to conventional ALS suggesting antigenic differences between lymphocytes and blast cells. We have shown that in certain experimental conditions, lymphocytes induced to proliferate are able to stimulate M L C t This research was supported by the Bureau of Medicine and Surgery Work Unit No. MR000.01.01.1066. The opinions or assertions contained herein are the private ones of the authors and are not to be construed as otficial or reflecting the views of the Navy Department or the naval service at large. :~On leave from the Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland. 121

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reaction of autologous resting lymphocytes (Green & Sell, 1970) and even to exert a cytotoxic effect on autologous cells (Ahmed, Jaroszewski & Sell, in preparation). We suggest that the "autoimmune" reaction of resting lymphocytes against autologous blast cells are not exceptional but take place continuously in the body, thus controlling immune responses. In the following we will attempt t o explain our concept of immune regulation using the available experimental data as they relate to T-cell function, B-ceU function and T-B-ceU co-operation in the immune response. 2. Basic Model

We assume that antigenic changes which occur on the surface of antigenreactive cells (ARC), in response to an antigen (X) and undergo blastt transformation, are specific for the antigen X. As depicted in Fig. 1, a new surface antigen y appears on the X-induced blast cell and triggers immune response of another ARC, specific for the new antigen y (ARCy). This response, which will be termed the regulatory anti-blast response (RABR), may result in production of anti-y memory cells and effector cells which either directly or by specific antibody inactivate any newly arising antigen X-specific blasts. However, since X-induced transformation of ARC to blast has to occur before y antigen is expressed on the blast, the RABR against antigen y

~ ARcx x or memorycell

AntigenX



__

Effecforcellx

. Antigeny

ARCy or memory cell y

, ~ ( ~ Memory cellx 4-Antigen y / ~ Effeclor cell y

T

X ~

Mereory cell y

Fro. 1. Schematic representation of the proposed mechanism of immune regulation. t We define here blast as a lymphocytewith surface antigens already changed following antigenic recognition.

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occurs subsequent to the response against antigen X. This delay allows for the production of effector cells and memory cells for antigen X before Xinduced blast cells are inactivated by the RABRy response. We postulate that the effector and memory ceils do not possess the same surface antigen y and, therefore, are not subject to the inhibitory effect of the RABR mechanism. The blast cells arising from the response of ARCy (which take part in RABR mechanism) themselves may be controlled by a similar mechanism until the ARC against subsequent blast-specific antigens are not available. A secondary stimulus with antigen X triggers proliferation of both memory cells (which arose during the primary immune response) and of virgin ARCs. When the latter reach the blast stage, a secondary response of RABR develops, which gives rise to effector cells y faster than during the primary response, causing the "primary" component of secondary immune response to be aborted. On the other hand, secondary blasts from memory cells, differentiating more quickly, thus may give rise to a new group of effector and memory cells before being affected by RABR control. Such a basic model provides a plausible explanation for several immune phenomena and permits some experimentally verifiable predictions.

3. B-T Lymphocyte Interaction If B lymphocytes after recognizing a specific antigen undergo blast transformation with antigenic changes and T lymphocytes recognize the new antigen y on the B blasts, an MLC type reaction could develop. Such an "MLC" may be the actual mechanism for T helper function in the stimulation of B lymphocytes to respond to thymus-dependent antigens. It is known that MLC supernatants may substitute for T helper cells in primary immune response in vitro (Dutton et al., 1971). Crucial proof for this phenomenon was provided by Talmage & Waiters (1974), who reported that nonadherent lymphocytes which had been stimulated with antigen for 5 hr and then blocked with mitomycin C can trigger an MLC reaction with lymphocytes from immune syngenic donors. Thus, the T cells engaged in immune response against newly exhibited antigens on B cells may function at early stages of the reaction as T helper cells. This could explain why T helper cells fail to adhere to solid phase antigens (Wigzell, 1970) since they are directed against blast-specific antigens. Since helper cells are specific for the carrier part of immunogen (for review, see Rajewsky & Pohlit, 1971), the prediction follows that at least some new membrane antigens exhibited on B blasts are also carrier specific.

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This could explain how T helper cells reacting to blast-specific antigens may give rise to MLC responses and induce mediators, thus supporting further differentiation of B blasts. It was noted that T-independent antigens, which do not require T helper assistance to evoke immune response, act also as B-cell mitogens (Coutinho & Miller, 1973; Strong, Ahmed, Seller, Knudsen & Sell, 1974). Their mitogenic properties may substitute for T helper assistance by providing stimulus necessary for differentiation of B blasts to respective antibody-producing ceils. However, recognition of new antigens on B blasts may still take place, thus enabling the efferent part of the RABR reaction to control B blast proliferation. It is known that T-cells may exert an inhibitory effect on immune response to thymus-independent antigens (Baker, Barth, Stashak & Amsbough, 1970).

4. IgM to IgG Switch

It has been suggested that the IgM to IgG switch in antibody production involves some signal being transmitted from T helper cells to B-cells responding to a given antigen (Katz & Benacerraf, 1972). We hypothesize that this is a second result of the specific interaction of T-cells with the carrier-specific new antigen y on B blasts. Thymus independent antigens which induce mainly 19s antibody response possess repetitive structural units (Katz & Benacerraf, 1972) with their cartier portion hidden under a dense coat of hapten. In this case, no carrier-specific change on B blast cells may occur. Therefore, helper-type interaction of T-cells with B blasts may not take place and the signal for IgM to IgG switch is not produced.

5. Ir Gene

We postulate that Ir gene controls the ability of T helper cells to recognize new carder-specific antigen on B blast surface. The immune response to (T,G)-A-L in mice beating responder Ir allele involves T-independent 19s antibody response to primary antigenic stimulation, but T-dependent secondary response, predominantly of 7s type (McDevitt, Bechtol, Grunet, Mitchell & Wegmann, 1971). The Ir gene seems to be expressed on T-cells (for review, see McDevitt, Bechtol & Hiimmeding, 1974). Differences in antibody production between responder and nonresponder mice are almost completely obliterated when foreign antigen as a carrier molecule is complexed with (T,G)-A-L (McDevitt, 1968), thus indicating a specific defect of helper T-cells. We postulate that this defect reflects inability of helper T-cells

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to recognize carrier-specific change on B-blast surface. It seems that in nonresponder animals the appropriate antigen acts as thymus-independent antigen while in the presence of Ir responder allele it acts as thymusdependent antigen.

6. Suppressor T-Cells, Tolerance Since tolerant individuals contain normal numbers of antigen-binding cells (Mitchell & Nossal, 1966) and lymphocytes of normal donors may exert cytotoxic activity toward autologous tissue, provided that no autologous serum is present (Cohen & Wekerle, 1973), there is no reason to suggest that there exist "tolerant cells", but tolerance maintaining mechanisms. Voluminous experimental data are available showing that autologous sera (e.g., Wegmann, Hellstr6m & Hellstr/Sm, 1971) and autologous cells other than ARC to particular antigen (e.g., Cohen & Wekerle, 1973) are responsible for maintenance of tolerance. We propose that tolerance results from the presence of memory RABR lymphocytes in an individual where there are no memory cells to a given antigen. Administration of the antigen results in an abortive primary immune response which does not result in formation of effector and memory cells, since preformed anti-blast antibodies are present or secondary RABR, developing faster, inactivates the new blasts. It has been shown that removal of a subpopulation of T-cells abrogates tolerance (Segal, Weinstein, Melmon & McDevitt, 1974). Abrogation of tolerance by cross-reactive antigens might be accounted for by the fact that highly specific RABR antibodies and killer cells may not recognize blasts with new surface antigens specific for the cross-reactive antigen. It is known that, in contrast to helper hctivity, the cytotoxic action of lymphoeytes is highly specific (Brunner & Cerottini, 1971). The origin of a tolerant state, including self-tolerance, may be related to factors which delay immune response to a would-be antigen (tolerogen) without delaying RABR against tolerogen-specific blasts. A number of laboratories have recently presented evidence for the suppressive effect of T-ceils on antibody production (for review, see Katz & Benacerraf, 1972). In our model, T suppressor cell corresponds to the RABR lymphocyte, capable of reacting against the new antigens on B blasts. A question arises whether, in our model, the T suppressor cells which interact with new antigens on B blast cells are formed from T helper cells or represent a separate line of differentiation. The available data show differences between T helper cells and T killer ceils in the expression of surface antigens (Kisielow, 1974), in adherence to insoluble antigen (Wigzell, 1970; Bach,

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Zier & Sondel, 1973) and in resistance to mycoplasma-caused injury (Eckner, Hart & Kumar, 1974) but only few results have been published on properties of T suppressor cells. They show similar radioresistance and sensitivity to anti-0 treatment of T helper and suppressor cells (Peavy & Pierce, 1974). We hypothesize, therefore, that T-helper and T-suppressor cells may be the same cell exerting its effects either through directly stimulating B blast cells or later by production of effector cells which can destroy the B blasts.

7. Suppressor B-Cells We anticipate that RABR may involve not only T-cell anti-B blast reaction, but also (1) B anti-T blast, (2) B anti-B blast, and (3) T anti-T blast reactions. Recent observations indicate that B cells may exert suppressive effect on cell-mediated immune reactions (Katz, Parker, Sommer & Turk, 1974; Neta & Salvin, 1974). The effect may result from antibody-response against new, immunogen-specific y antigen on T blasts. The unavailability of data indicating B-cell suppression of B-ARC function in the absence of T-cell function, may be explained if the B-ARC anti-B blast antibody response is thymus-dependent and, therefore, also requires T-cell presence. This could explain the suppressive effect of T-cells on antibody response to thymus-independent antigens. In such a response, no T-B helper interaction takes place and, therefore, in line with our hypothesis, no direct T-cell suppressor activity should take place. However, T-cells may control indirectly by influencing the production of B-ARC anti-B blast ceils. Since T suppressor cells were found to suppress in vitro MLC response (Folch & Waksman, 1974b), response to T-cell mitogens (Folch & Waksman, 1974a) and generation of cytotoxic lymphocytes (Peavy & Pierce, 1974), it is conceivable that the T anti-T blast type of RABR may also be operative in regulating immune responses.

8. Allogenic Effect The importance of timing of allogenic cells injection in relation to first antigen injection (6 days after antigen) for obtaining optimal stimulation of antibody production (Katz, 1972) is in line with our suggestion that allogenic ceils inactivate or kill effector T ceils specific for y antigen on blast ceils and thus augmenting the antibody response to the antigen in question. A similar mechanism may be responsible for breaking tolerance by allogenic cells (McCuUagh, 1972).

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9. Immune Tests in vitro In view of the current use of various in vitro tests in cellular immunology, it is important that our model can serve to explain certain experimental results. In the case of antigen-induced proliferation of lymphocytes in fetal calf serum, transformation of ARCs to blasts may cause an MLC reaction against these blasts. This seems to us a good alternative explanation of much higher numbers of activated cells in the cultures than expected, on the basis of clonal theory, to the existence of mitogenic factor. MLC reactions require close contact between lymphocytes in order to permit recognition and stimulation of the responder cells by the surface antigens. If the stimulation of lymphocytes by mitogens or antigens did not require a secondary cell-to-cell interaction, then close contact of cells or clumping of cells should not be required to permit a maximal response. However, it has been noted that cell clumping is required to get a maximal response following antigen or mitogen stimulation (Peters, 1972). This finding is consistent with our hypothesis that the augmentation of the initial response to an antigen or mitogen is the result of a subsequent response of an MLC nature between an antigen reactive cell and a B-blast cell which now has a new "y" antigen on its surface. This secondary MLC type response could cause a marked augmentation of the original reaction against antigen or mitogen. MLC reactions can be inhibited by anti-HLA antibody (Cerottini & Brunner, 1974). If the augmentation of the total response produced by mitogen required a subsequent MLC response, such as the one we have described, it would seem reasonable that anti-HLA antibody also might inhibit the maximum production of response against both antigen and mitogen. This, in fact, is the case, lending further credibility to the concept of anti-blast MLC reactions occurring as a consequence of transformation produced by antigen or mitogen. 10. Conclusions

We have presented a model for the antigen-specific control of immune responses. The model is based on the assumption that immunogen recognition results in appearance on the blast surface of new antigenic determinants (y) specific for the immunogen. The new antigenic determinants are recognized by another set of lymphocytes and triggers differentiation of the latter to memory cells and effector cells. These effector cells are capable of inactivating blast cells triggered by original immunogen. The model provides a plausible interpretation of T and B lymphocyte co-operation, tolerance, suppressor function of lymphocytes and some other immune phenomena.

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The suggested model is selective in the sense that ARCs react only with immunogens to which they carry genetically programmed receptors. It is also instructive since it is proposed that at least some new antigens on B blast surface are carder-specific, whereas the precursor of B blast is specific, not for the carrier, but for the "haptenic" part of the immunogen. One could suggest that the new antigen, which is carrier-specific and present only after antigenic recognition, may be the carder part of the immunogen molecule itself, "implanted" close to histocompatibility antigens on the blast cell. This, however, is inconsistent with the inability to absorb helper cells on insoluble carriers and suggests that the new y antigen is not identical to the carrier antigen. More probably, the new antigen reflects immunogen-induced change in the expression of surface antigens determined by genes known to be responsible for stimulation of MLC and cell-mediated lymphotoxicity (CML) in allogenie systems. It was suggested previously that an evolutionary homology exists between genes for histocompatibility antigens and immunoglobulin genes (Burnet, 1970; Bodmer, 1972; Gaily & Edelman, 1972). Molecular similarity of f12 microglobulin, homologous with Ch3 constant region of IgG and HL-A antigens (Peterson, 1973) may indicate that products of histoeompatibility complex also consist of a constant and variable portion. The latter, following antigen recognition, may be the target of RABR mechanism. It should be added that, apart from the antigen-specific new "y" determinants on the surface of a blast, several other determinants may appear. Reactions of other lymphocytes against such antigen-nonspecific determinants could provide a nonspecific mechanism of control of immune responsiveness. The suggested mechanism of immune regulation and co-operation of humoral and cell-mediated immune responses do not aim at replacing previously suggested mechanisms, but rather at bridging some of the gaps in the interpretation. Critical remarks of Dr N. R. Rose, Dr G. J. V. Nossal and Dr W. Leibold are gratefully acknowledged. REFERENCES AHMED, A., JAROSZEWSKI,J. & SELL, t . W. In preparation. BACH, F. H., ZIER, K. S. & SONDEL,P. M. (1973). Transplant. Proc. 5, 1717. BAKER,P. J., BARTH,R. F., STAS•AK, P. W. & AMsaouon, D. F. (1970). J. Immtm. 104, 1313. BOD~R, W. F. (1972). Nature, Load. 237, 139.

B~rsCnER, P. A. (1972) Transplant. Rev. 11, 217. BI~rSC~R, P. A. & Comq, M. (1968). Nature, Load. 220, 444. BRUN~R, K. T. & CEROTntql,J. C. (1971). In Progress ia Immunology (B. Amos, ed.) p. 385. New York & London: Academic Press. Bumq~-r, F. M. (1970). Nature, Load. 226, 123.

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Mechanism for regulation of immune responses.

J. theor. Biol. (1976) 57, 121-129 Mechanism for Regulation of Immune Responses~ JAN JAROSZEWSKI,~ AFTAB AI-IMED AND KENNETH W. SELL Department of C...
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