An antibody-secreting B cell hybridoma, KJ1-26.1, has been prepared from mice immunized with the T cell hybridoma DO-11.10, which recognizes chicken ovalbumin in association with I-Ad (cOVA/I-Ad). KJ1-26.1 blocks I-restricted antigen recognition by DO-11.10 and a subclone of this T cell hybridoma, DO-11.10.24, which has the same specificity for cOVA/I-Ad as its parent. KJ1-26.1 does not block I-restricted antigen recognition by any other T cell hybridoma tested, including a number of T cell hybridomas closely related to DO-11.10, with similar, but not identical, specificities for antigen/I. Moreover, KJ1-26.1 binds to DO-11.10 and DO-11.10.24, but not to any other T cell hybridomas tested, including three subclones of DO-11.10 that have lost the ability to recognize cOVA/I-Ad. Thus, in every regard KJ1-26.1 appears to be binding to all or part of the receptors for antigen/I on the T cell hybridoma DO-11.10. KJ1-26.1 appears to bind to approximately 15,000 molecules/cell on the surface of DO-11.10. The antibody precipitates an 80,000 dimer from the cells, which on reduction migrates as 40-44,000 monomers. The receptor(s) for antigen/I on DO-11.10 therefore includes molecules with these properties.

https://rupress.org/jem/article-pdf/157/4/1149/1093336/1149.pdf

The major histocompatibility complex-restricted antigen receptor on T cells. I. Isolation with a monoclonal antibody.

Although the passive transfer of T cell-mediated immunity to growth of a tumor implant is relatively easy to demonstrate, it has proven extremely difficult to demonstrate that passively transferred, tumor-sensitized T cells have any therapeutic effect against an established growing tumor (1). The most likely reason for the refractoriness of established immunogenic tumors to adoptive immunotherapy with tumor-sensitized T cells was supplied by previous publications from this laboratory (2, 3), which show that progressive growth of an immunogenic tumor evokes the generation in its host of a T cell-mediated mechanism of immunosuppression. The existence of this mechanism of immunosuppression was revealed in two ways: first, by showing that although passively transferred, tumor-sensitized T ceils failed to cause the regression of tumors growing in normal mice, they caused the complete and permanent regression of the same-sized tumors growing in mice that had been made T cell deficient by thymectomy and irradiation; and second, by demonstrating that failure of passively transferred, sensitized T cells to cause the regression of tumors in normal mice was associated with the presence in these mice of splenic T cells capable of inhibiting adoptive T cell-mediated regression of tumors growing in T cell-deficient mice. On the basis of this and other evidence, it was hypothesized (2, 3) that the progressive growth of an immunogenic tumor evokes the generation of a state of T cell-mediated concomitant immunity that undergoes T cell-mediated negative regulation before enough effector T cells are produced to destroy the tumor. It was further hypothesized (4) that any attempt to cause tumor regression by the passive transfer of tumor-sensitized T cells represents an attempt to superimpose an adoptive immune response on an already ongoing concomitant immune response that may be undergoing negative regulation, depending on the size of the tumor. If this line of reasoning is correct, it should follow that any treatment that prevents the generation of concomitant immunity and of the suppressor T cells that negatively regulate it, should facilitate the antitumor function of passively transferred, tumor-sensitized T cells. The purpose of this paper is to show that a cyclophosphamide-treated, tumorbearing recipient can substitute for a T cell-deficient, tumor-bearing recipient for demonstrating that an established tumor can be caused to completely regress by the * Supported by grant CA-16642 from the National Cancer Institute, grant IM-266 from the American Cancer Society, and grant RR-05705 from the Division of Research Resources, National Institutes of Health.

Cyclophosphamide -facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced

Autoimmune oophoritis that develops in A/J mice after neonatally thymectomy (NTx) was prevented by a single intraperitoneal injection of spleen cells or thymocytes from normal adult female mice. Prevention of oophoritis was achieved when spleen cells were given within 2 wk after Tx. When spleen cells were obtained from neonatally oophorectomized mice, four times more cells were required for the prevention of oophoritis, but those from the mice oophorectomized on day 7 after birth had equivalent capacity to prevent oophoritis to those from normal female mice. The spleen cells from normal A/J mice that prevented the development of oophoritis in NTx A/J mice were Thy-1+, Lyt-1+,23-, Ia-, Qa-1-, sensitive to in vitro irradiation with 400 rad, resistant to administration of cyclophosphamide or anti-thymocyte serum, and were not eliminated by adult thymectomy. Thymocytes with oophoritis-preventing capacity were also found to be Lyt-1+,23- and TL-1,2,3-. These results seem to correlate well with the finding that the Lyt-1 subpopulation is substantially decreased in NTx mice. The results suggest that, in this post-thymectomy autoimmune oophoritis, NTx abrogates the Lyt-1 T cell subpopulation that serves as suppressive or regulatory cells over developing self-reactive cells directed toward ovarian antigens, and eventually may cause autoimmune oophoritis.

https://rupress.org/jem/article-pdf/156/6/1577/1093068/1577.pdf

Study on cellular events in post-thymectomy autoimmune oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oophoritis.

Two major facts about T lymphocytes have become apparent over the past 20 years: first, as demonstrated by the early work of Claman & Chaperon [10], Davies [13] and Miller & Mitchell [36] for helper function and Gershon [28] for suppressor function in humoral responses, a key activity of T cells is to serve as regulators of immunity; second, as initially described by Cantor, Boyse and associates [6,9], the peripheral T-cell pool is very heterogeneous, consisting of a large number of subsets, each with distinct differentiation naarkers and immunologic functions. Intensive investigation of the regulatory phenomenon of specific immune suppression has revealed the importance of multiple interactions among these T-cell subsets in even this limited aspect of cellular immune responses [1, 17, 20, 26, 35, 45, 50, 52, 63, 65, 67]. During the course of these studies, several distinct model systems have been used to examine T-cell-mediated suppression, and, as a result, several related but clearly nonidentical suppressor regulatory pathways consisting of a variety of T-T interactions have been described, involving cells with different phenotypes and soluble suppressor factors with various immunochemical and biological properties. These data raise the important question as to whether there are many different pathways of T-cell-mediated suppression, or whether the described pathways are fragments of a larger single sequence. During the past several years, these laboratories have studied in detail several different suppressor T-cell (Ts) models involving both humoral and cell-mediated immunity [26, 45, 50, 65, 67] in an effort to define the molecular basis of antigen-specific T-cell recognition and cell-cell communication. Recent findings in these systems have suggested to us the possibility of integrating the great majority of results on T-cell suppression into a single overall scheme that eliminates many key differences between the several model systems. This review is an attempt to summarize briefiy the best-defined systems of immune suppression and to suggest an integration of these data into a major suppressor pathway.

A Single Major Pathway of T-Lymphocyte Interactions in Antigen-Specific Immune Suppression

In this article we speak about the network of idiotypes in the immune system. We start by defining the vocabulary we are going to use. We then discuss the structural basis of idiotypic determinants (i.e. antigenic determi­ nants on the antibody variable region; also called idiotopes) and of their complementary anti-idiotypic antibody binding sites (anti-idiotopes). Idi­ otopes and anti-idiotopes are encoded by antibody V, D, and J genes. The idiotypic repertoire thus reflects the repertoire of these genes as they are expressed, selected, and somatically modified in the immune system. The idiotypic repertoire, its genetic basis and its selection in ontogeny, is a main theme of the present view. This relates directly to the functional idiotypic network: Which rules do idiotypic interactions in the immune system follow and what is their physiological role? We will see that idiotypic interactions seem to be involved in the growth control of lymphocyte clones with defined receptor specificity and may thus be essential for the generation of a diverse system of interacting cells. They also stabilize the expression of a given receptor repertoire in active immune responses. Idiotypic interactions occur within the compartment ofB lymphocytes, but they also involve T cells. We discuss the crucial issue of whether or not recognition of B-cell idiotypes is one of the principles by which T cells are selected in the immune system. This article cannot deal with all facets of idiotypic research. We restrict ourselves largely to the discussion of experimental work in the mouse and, in particular, we do not discuss in any detail the role of idiotypic interac­ tions in regulatory T-cell circuits controlling immune responses. Detailed models of immunologic control through cell interactions have emerged from recent work in this field. We refer the disappointed reader to a few

Genetics, Expression, and Function of Idiotypes

Administration of azobenzenearsonate (ABA)-coupled syngeneic spleen cells intravenously to A/J mice leads to the generation of suppressor T cells (Ts1) which exhibit specific binding to ABA-bovine serum albumin (BSA)-coated dishes. These Ts1 share idiotypic determinants with the major cross-reactive idiotype (CRI) of the anti-ABA antibodies of A/J mice, and also produce a soluble suppressor factor (TsF) bearing CRI and I-J subregion-coded determinants. Injection of this TsF into naive A/J mice elicits a second set of specific suppressor cells (Ts2) which are not lysed by anti-CRI antibody plus C, and which do not bind to ABA-BSA-coated dishes. However, in contrast with Ts1, these Ts2 do bind to plates bearing CRI+ anti-ABA immunoglobulin. Thus, Ts2 exhibit anti-idiotypic specificity. These data indicate that antigen elicits the production of a soluble T cell product bearing both variable portion of the Ig heavy chain (VH) and I-J subregion-coded determinants which serves to communicate between T cell subsets to establish an idiotype-anti-idiotype regulatory pathway.

/pdf/antigen-and-receptor-driven-regulatory-mechanisms-iv-2nyawaynnq.pdf

Antigen- and receptor-driven regulatory mechanisms. IV. Idiotype-bearing I-J + suppressor T cell factors induce second-order suppressor T cells which express anti-idiotypic receptors

Azobenzenearsonate (ABA)-specific T cell-derived suppressor factor (TsF1) from A/J mice was used to induced second-order suppressor T cells (Ts2). Comparison of suppressor T cells induced by antigen (Ts1) with Ts2 induced by TsF1 revealed that Ts1 were afferent suppressors active only when given at the time of antigen priming, and not thereafter, whereas Ts2 could act when transferred at any time up to 1 d before antigen challenge for a delayed-type hypersensitivity response. This was true even when the recipient could be shown to be fully immune before transfer of Ts2, thus defining these cells as efferent suppressors. The anti-idiotypic specificity of the Ts2 was demonstrated by the ability of Ts to bind to idiotype (cross-reactive idiotype [CRI])-coated Petri dishes. A soluble extract from Ts2 (TsF2) was also capable of mediating efferent suppression that was functionally antigen- (ABA) specific. Comparison of TsF1 with this new factor, TsF2, revealed that both lack Ig-constant-region determinants, possess H-2-coded determinants, and show specific binding (to ABA and to CRI+-Ig, respectively). TsF1 acts in strains that differ with respect to H-2 and background genes, whereas TsF2 shows H-2- and non-H-2-linked genetic restrictions. This existence of H-2 restriction of TsF2 activity suggests that the apparent discrepancies in studies of H-2 restriction of TsF may be a result of the analysis of two separate classes of TsF, only one of which shows genetically restricted activity, thus unifying several models of suppressor cell activity.

/pdf/antigen-and-receptor-driven-regulatory-mechanisms-vii-h-2-3uyi4hpwjb.pdf

Antigen- and receptor-driven regulatory mechanisms. VII. H-2-restricted anti-idiotypic suppressor factor from efferent suppressor T cells.

A/J anti-p-azobenzenearsonate (ABA) antibodies bearing cross-reactive idiotypic (CRI) determinants, when coupled to spleen cells and then injected intravenously into naive animals, stimulate suppressor T cell (Ts) responses. Moreover, previous studies have demonstrated that the ability of such idiotype-coupled spleen cells to induce immune unresponsiveness to subsequent immunization with ABA-coupled spleen cells is linked to Igh-1 genes. Thus, CRI bearing antibodies from A/J mice, when conjugated to normal BALB/c spleen cells in vitro and then injected intravenously to syngeneic BALB/c mice, failed to induce tolerance in these animals. However, spleen cells taken from these animals transferred significant degrees of suppression to Igh-1 congenic C.AL-20 but not to H-2 congenic, Igh-1 distinct B10.D2 mice. Therefore, the failure of CRI-coupled spleen cells to induce suppressor cell- mediated unresponsiveness in animals unable to express the appropriate VH genes (i.e. BALB/c and B10.D2) appears to be caused by the lack of idiotype- matched targets. The notion that the ability to express certain Vn genes in the recipient animal is a prerequisite for suppressor cell function was further supported by the observation that suppressor cells induced in C.AL-20 mice failed to transfer any degree of suppression to BALB/c mice. The ability to transfer suppression from BALB/c mice to C.AL-20 mice is a T cell- dependent phenomenon, since in vitro treatment with anti-Thy 1.2 antiserum and complement completely abrogated suppressor cell function. Furthermore, these suppressor T cells are antigen specific and can be enriched on idiotype-coated petri dishes, indicating they possess anti-idiotypic receptors. Therefore, appropriate anti-idiotype and idiotype interaction is essential for the manifestation of suppressor T cell function in ABA-specific suppressor pathways.

/pdf/antigen-and-receptor-driven-regulatorymechanisms-the-failure-3zj475vpt7.pdf

Antigen- and receptor-driven regulatorymechanisms. The failure of idiotype- coupled spleen cells to induce unresponsiveness in animals lacking the appropriate VH genes is caused by the lack of idiotype-matehed targets

The first detectable suppressor T cell (Ts) arising after i.v. administration of azobenzenearsonate- (ABA) conjugated syngeneic spleen cells to A/J mice has been studied for its receptor specificity and ability to produce soluble suppressor factor(s). This cell, termed Ts1, has a specific receptor for the eliciting antigen ABA, as demonstrated by selective binding to ABA protein- but not TNP protein-coated plastic dishes. The activity of ABA-Ts1 can be abrogated by treatment with anti-idiotypic antibodies made against anti-ABA antibodies of A/J mice (anti-CRI), indicating that these ABA-binding cells possess a surface receptor structure sharing idiotypic determinants with antibodies of the same specificity. Finally, soluble extracts from, antigen-adherent ABA-Ts1, but not nonadherent cells from the same spleen cell population, possess suppressive activity when assayed directly for afferent suppression or tested for their ability to trigger a second population of Ts (Ts2) in naive recipients. These findings demonstrate a close concordance between a T cell surface receptor, soluble T suppressor factors, and B cell derived antibody, all capable of direct recognition of the eliciting ABA antigen.

Antigen and receptor-driven regulatory mechanisms. VI. Demonstration of cross-reactive idiotypic determinants on azobenzenearsonate-specific antigen-binding suppressor T cells producing soluble suppressor factor(s)

M H Dietz

Papers

Antigen- and receptor-driven regulatory mechanisms. IV. Idiotype-bearing I-J + suppressor T cell factors induce second-order suppressor T cells which express anti-idiotypic receptors

Antigen- and receptor-driven regulatory mechanisms. VII. H-2-restricted anti-idiotypic suppressor factor from efferent suppressor T cells.

Antigen- and receptor-driven regulatorymechanisms. The failure of idiotype- coupled spleen cells to induce unresponsiveness in animals lacking the appropriate VH genes is caused by the lack of idiotype-matehed targets

Antigen and receptor-driven regulatory mechanisms. VI. Demonstration of cross-reactive idiotypic determinants on azobenzenearsonate-specific antigen-binding suppressor T cells producing soluble suppressor factor(s)