Interaction of Ia-molecule of specific T-suppressor with complementary structure of syngeneic responding T-lymphocyte

To achieve inhibition of proliferation of alloantigen-induced T-lymphocytes in mixed lymphocyte culture by specific suppressor T cells (SSTC), identity of SSTC and responder in MHC class II antigens is required; either in IC or in IA + IE. By shielding of the SSTC with antiserum to ICd product (without complement), it is demonstrated that ICd product is expressed on the SSTC surface only, rather than on the surface of both stimulator and responder cells (native or preactivated with the alloantigen). Pretreatment of SSTC with anti-ICd antibodies in the absence of complement does not prevent specific SSTC interaction with the alloantigen, but prevents the SSTC function in reversible fashion. Because part of responders preactivated with an alloantigen acquired a capacity to adhere to the syngeneic SSTC monolayer, it is supposed that a receptor to the syngeneic Ia-molecule of SSTC membrane arises on the surface of preactivated responder T cells, which results in direct interaction between these two cells, reflecting the "interactional restriction" mechanism of SSTC function.     

Requirement for the location of both appropriate and irrelevant H-2 antigens on the same stimulator cell for unspecific DNA-synthesis inhibition by the H-2-antigen-primed,specific suppressor T cells

Specific suppressor T cells (SSTC), primed in vivo with H-2 antigens, have been shown previously to inhibit DNA synthesis in the one-way, three-cell mixed lymphocyte reaction (MLR) provided that (a) the stimulator cells bear the priming H-2 antigens, and (b) the responder cells possessIC+S regions homologous to those of the SSTC. Anti-B10.A BlO.A(2R) SSTC (anti-D^d) and anti-A.AL A.TL SSTC (anti-K^k) are shown here to be able to inhibit the DNA synthesis triggered in MLR, not only by the corresponding antigens, D^d and K^k, respectively, but also by irrelevant, third-party H-2 and Mls products provided that the corresponding and third-party antigens are presented on the same stimulator cell. If stimulatorH-2 regions, whose products interact with SSTC and responders, are located on different stimulator cells within the particular MLR, SSTC activity is not elicited. Participation of cytotoxic T lymphocytes in DNA-synthesis suppression is ruled out. Direct contact or location of the inhibited responder cell very close to SSTC is considered to be required for the development of SSTC activity.     

Production of monoclonal antibodies to antigens of specific mouse T-suppressors

F1(MSU X WAG) rats were immunized with anti B6 BALB/c specific suppressor T cells (SSTC), purified by absorption/elution technique, with the following fusion of splenocytes to NS-I myeloma cell line. Hybrids were screened for their ability to affect SSTC, cytotoxic T lymphocytes (CTL) and producers of macrophage migration inhibition factor (MIF-producers) all triggered by in vivo priming with allogeneic cells. Two hybridoma cell lines--C1 and C4 inactivated SSTC by approximately 50%, leaving CTL and MIF-producers intact. C4 were also active in vivo, if injected as ascitic fluid from nu/nu mice, though to a lesser extent than in vitro.     

Induction in vivo of specific T suppressors in mice of mutant lines H-2KbT

The differences in the generation of specific suppressor T cells (SSTC) against H-2Kb wild type were investigated in H-2Kbm1, H-2Kbm3 and H-2Kbm4 mutants. Anti-Kb SSTC were produced only by bm3 mutant and F1(BALB/c X bm3) hybrid. T-cell nature of SSTC of bm3 mutant was confirmed by anti-Thy 1.2 monoclonal antibodies described in the same study.     

Studies on the mechanism of stimulation of T cells by the Mycoplasma arthritidis-derived mitogen. Role of class II IE molecules

A mitogen derived from the supernatant of broth cultures of Mycoplasma arthritidis (MAS-P) stimulates a proliferative response by normal, unprimed T cells and interleukin 2 production by some, but not all, T cell hybridomas. The response requires an IE-positive accessory cell (AC). The direct participation of IE, and not IA, in this system was confirmed by two sets of experiments. First, L cells transfected with IE, but not IA, provided effective AC function for both normal T cells and the T cell hybridoma DO-11.10. Second, we have taken a more direct approach by showing that purified IE incorporated in liposomes and used to coat glass beads can support the MAS-P response of the DO-11.10 T cell hybridoma in the absence of intact AC or other AC molecules. Although the receptor for IE-MAS-P has not been identified, we have eliminated from consideration two potential T cell recognition structures. Monoclonal antibody to the antigen-major histocompatibility complex specific receptor failed to inhibit the MAS-P response of DO-11.10 or the T cell line LBRM-33. Furthermore, the L3T4 molecule did not appear to be involved since an L3T4-negative variant of DO-11.10 responded well to the mitogen. In addition, we show that both Lyt-2-positive and L3T4-positive T cells respond to this class II-restricted stimulus. Thus, we postulate the existence of a non-T cell receptor, non-L3T4 receptor that recognizes MAS-P in association with a presumed nonpolymorphic region of IE.     

Regulation of the human allogeneic proliferative response in vitro

It has previously been shown that presensitized cells in culture medium release suppressor factors (SF) which can inhibit a primary mixed leukocyte reaction (MLA I). This occurs when the presensitized cells are resensitized with an HLA-DR-specific cell, which can be either the primary stimulator or any other DR-identical allogeneic cell. The autologous responders (SF producer cells) and certain allogeneic cells are suppressed, which suggests that restriction takes place. In this paper the effect of preincubation of responder or stimulator cells in SF has been studied: (1) When unprimed responders are preincubated with the suppressor supernates (SF) and tested in MLR I against several stimulators, the cells of the autologous SF producer and certain other allogeneic cells are always inhibited as already observed when SF was added directly to a mixed lymphocyte culture. (2) When the same stimulators are preincubated with the same SF and used as stimulators with the same responders (not preincubated) then inhibition is observed without restriction. This difference in behavior suggests the existence of at least two factors, one acting directly but only on some responders (restricted factor) and the other acting through stimulators on all responders. (3) Filtration of unprimed responders through glass wool (before SF preincubation and coculture with stimulators in MLR I) produces nonadherent T cells which are suppressed more after preincubation with SF than the same cells unfiltrated. This could be due to the existence of a subset of acceptor cells. (4) None of these factors has immunoglobulin characteristics. Their molecular weights are between 40 000 and 70 000 daltons.Abbreviations used in this paper SF suppressor factor - CF control factor - MLR I primary mixed lymphocyte reaction - MHC major histocompatibility complex - MLR II secondary mixed lymphocyte reaction - CML cell-mediated cytotoxicity assay - PHA phytohemagglutinin - ⁵¹Cr chromium 51     

Mapping of SJL/J reticulum cell sarcoma tumor-associated Ia antigens by T cell hybridomas: characterization of tumor-specific and shared epitopes detected on IE+ allogeneic cells

Previous studies have suggested that reticulum cell sarcoma (RCS) tumor cells of SJL/J (IA + IE-) mice express neospecificities that are related to antigenic specificities characteristic of IE+ allogeneic cells. These neospecificities have also been suggested to play a role in the strong syngeneic antitumor proliferative response as well as in regulating RCS growth in vivo. The present studies characterize four RCS tumor-specific T cell hybridoma clones prepared from the fusion of BW5147 thymoma with T cells derived from lymph nodes of tumor-bearing mice. Upon stimulation, these hybridomas secrete IL 2 in the supernatant. Two hybridomas responded to RCS to IE+k and to IE+d allogeneic cells, respectively, and the other two hybridomas were tumor specific. The specificity of these hybridomas was assessed by response to both spontaneous and transplantable RCS lines and failure to stimulate a response by either normal or LPS-induced B cell blasts from the host SJL/J cells. The epitopes recognized by the T cell hybridomas were examined by the ability of several monoclonal antibodies to inhibit the IL 2-induced response by the T cell hybridomas. Antibodies directed against the IABs polypeptide of the IA hybrid molecule blocked the antitumor response by all four hybridomas. However, the response to allogeneic IE+ cells was not blocked by anti-IAs antibody but was blocked by antibodies directed against either the IAk,d or IEk,d hybrid molecules or the corresponding alpha- or beta-chains. The response to both RCS and allogeneic cells was blocked by monoclonal antibodies directed against L3T4 antigens on the T cells. Based on the exquisite specificity of the T cell receptors, the results here demonstrate that RCS tumor cells express on their surface both tumor-specific I-A-associated epitopes and Ia-associated antigenic specificities that are shared with IE+ allogeneic cells. The present studies of adapting T cell hybridomas and blocking antibodies proved useful to characterize and map distinct tumor-associated epitopes on the surface of tumor cells. These findings, when combined with structural studies, should help unravel the molecular complexity of tumor-associated antigens.     

The role of regulatory components from resident T lymphocytes in polyclonal B cell activation

Resident T lymphocytes have been found to exert helper and suppressor regulatory influences with regard to polyclonal activation of murine splenic B lymphocytes elicited by lipopolysaccharide. In the normal adult spleen, only T cell helper influences are exercised over polyclonal B cell activation. This activity is a property of Lyt 1+2- T cells and does not appear to be subject to MHC restriction. Suppressive influence evidently is either latent or it exists at such a low level that its effects are difficult to detect. No regulatory activity can be recovered from the supernatants of T cells, cultured either with or without LPS. However, suppressor T cell function may be evoked by activating splenic T cells with Concanavalin A or by sonicating unstimulated splenic T cells in order to liberate a suppressive potential which is not expressed by these unstimulated cells when intact. The soluble fraction of resident splenic T cell sonicates exerts both helper and suppressor regulatory influences. The soluble helper activity is derived from Lyt l+2- T cells, whereas suppressor activity is generated from Lyt 1-2+ T cells. The suppressive activity of T cell sonicates is not restricted by the MHC gene complex. Helper and suppressor activities contained in splenic T cell sonicates were separated by gel chromatography; the suppressive activity was found to elute with a molecular weight between 68,000 and 84,000 daltons, and the helper activity eluted with a molecular weight between 15,000 and 23,000 daltons. The data indicate that helper and suppressor activities are distinct molecular entities derived from distinct splenic T lymphocyte subpopulations. The possibility that these molecules are precursors to or components of antigen-specific or nonspecific helper and suppressor factors described in the literature is discussed.     

Relationships between antigen-specific helper and inducer suppressor T cell hybridomas

Ts1, or inducer suppressor T cells, share many phenotypic and functional characteristics with helper/inducer subset of T cells. In order to evaluate the relationship between these cell types, we made a series of new Ts1 hybridomas by the fusion of Ts1 cells with the functionally TCR alpha/beta-negative BW thymoma (BW 1100). Three Ts1 hybridomas (CKB-Ts1-38, CKB-Ts1-53, and CKB-Ts1-81) were established that express TCR and produce Ag-specific suppressor factors constitutively, thus making it possible to study the nature and specificity of Ag receptors, MHC restriction, and lymphokine production by the Ts1 hybridomas. Results presented in this report demonstrate that all the Ts1 hybridomas described here express CD3-associated TCR-alpha beta. These three Ts1 hybridomas recognize Ag (NP-KLH) specifically in a growth inhibition assay and this recognition is restricted by IE molecules. Two of the hybridomas also produce IL-2 or IL-2 and IL-4 upon Ag-specific activation. Thus, by these three criteria the Ts1 hybridomas appear indistinguishable from Th cells. These three Ts1 hybridomas, however, release suppressor factors (TsF1) in the supernatant that suppress both in vivo DTH and in vitro PFC responses in an Ag-specific manner. Like the TsF1 factors characterized previously, the suppression mediated by these factors are Igh restricted and lack H-2 restriction. These factors mediate suppression when given in the induction phase but not during the effector phase of the immune response. The TsF1 factors are absorbed by Ag (NP-BSA), and anti-TCR affinity columns and the suppressor activity can be recovered by elution. The data are consistent with the interpretation that Ts1 inducer-suppressor T cells are related to Th cells; the feature that distinguishes these cells is the ability to produce Ag-binding factors that specifically suppress immune responses.     

Modulation of the immunosuppressive effects of splenic macrophages in Fischer rats bearing adenocarcinoma 13762

Summary The nature of spleen cells in Fischer rats bearing a large size (>1 cm diameter) mammary adenocarcinoma 13762A (MAC) which block the immunostimulating capacities of MTP² (a synthetic immunomodulator) and suppress proliferation in vitro of splenic T and B lymphocytes by their respective mitogens was investigated. Splenic macrophages were recognized as the suppressor cells by (a) restoration of mitogenic responses by depletion of macrophages from spleen cell suspensions and (b) continued suppressor activity in spleen cell suspensions of tumor bearers devoid of viable T lymphocytes. Macrophage contact with T lymphocytes was required for the inhibition of T lymphocyte proliferation by concanavalin A as shown by (a) the absence of suppressor activity in supernatants derived from cultured suppressor macrophages, (b) lowering of the suppressor activity of intact macrophages after treatment with neuraminidase, (c) lowering of the suppressor activity of macrophages by addition of red cells to spleen cultures of tumor bearers indicating red cell interference with macrophage-T cell interaction and (d) lack of inhibiting action of suppressor macrophages on allogenic T lymphocyte proliferation showing macrophage T cell recognition for suppression.Animals bearing a large size tumor exhibited spleen hypertrophy and an increase in macrophage:lymphocyte ratio and a decrease in red cell:lymphocyte ratio. Splenic macrophages did not appear to be implicated in blocking antitumor immunity induction since (a) suppressor macrophages were absent in spleens during the inductive phase of the immune response and (b) MAC implanted in allogenic Wistar rats grew to about 2 cm diameter, induced splenic suppressor macrophages but the tumor was later rejected by the animals. Collectively the results suggest that suppressor macrophages are the result of increasing tumor volume rather than its cause.This study was supported by a grant from the National Cancer Institute of Canada Abbreviations used: Con A, Concanavalin A; LPS, lipopolysaccharide; PHA, phytohemagglutinin; MTP, maltose tetrapalmitate; MAC, mammary adenocarcinoma 13762; RPMI, Roswell Park Memorial Institute; TBR, tumor bearing rat; RBC, red blood cell     

gamma delta+ T cells regulate major histocompatibility complex class II(IA and IE)-dependent susceptibility to coxsackievirus B3-induced autoimmune myocarditis.

Coxsackievirus B3 (CVB3) infection induces myocardial inflammation and myocyte necrosis in some, but not all, strains of mice. C57BL/6 mice, which inherently lack major histocompatibility complex (MHC) class II IE antigen, develop minimal cardiac lesions despite high levels of virus in the heart. The present experiments evaluate the relative roles of class II IA and IE expression on myocarditis susceptibility in four transgenic C57BL/6 mouse strains differing in MHC class II antigen expression. Animals lacking MHC class II IE antigen (C57BL/6 [IA+ IE-] and ABo [IA- IE-]) developed minimal cardiac lesions subsequent to infection despite high concentrations of virus in the heart. In contrast, strains expressing IE (ABo Ealpha [IA- IE+] and Bl.Tg.Ealpha [IA+ IE+]) had substantial cardiac injury. Myocarditis susceptibility correlated to a Th1 (gamma interferon-positive) cell response in the spleen, while disease resistance correlated to a preferential Th2 (interleukin-4-positive) phenotype. Vgamma/Vdelta analysis indicates that distinct subpopulations of gamma delta+ T cells are activated after CVB3 infection of C57BL/6 and Bl.Tg.Ealpha mice. Depletion of gamma delta+ T cells abrogated myocarditis susceptibility in IE+ animals and resulted in a Th1-->Th2 phenotype shift. These studies indicate that the MHC class II antigen haplotype controls myocarditis susceptibility, that this control is most likely mediated through the type of gamma delta T cells activated during CVB3 infection, and finally that different subpopulations of gamma delta+ T cells may either promote or inhibit Th1 cell responses.     

Mechanism of histamine-induced inhibition of lymphocyte response to mitogens in mice

Histamine induced, in mice, an inhibition of lymphocyte response to PHA and LPS, at molar concentrations ranging from 10^?3 to 10^?9M. This inhibition occurs as a specific interaction between histamine and T lymphocytes bearing H2-type receptors for this hormone (H + cells) and Ly 2 membrane antigens. Two features of the suppressive activity of this T-cell subpopulation were observed: (i) when histamine is added at the beginning of the culture period with PHA or LPS, it activates the suppressor activity of H + cells which act on the lymphocyte population responding to PHA and LPS; (ii) preincubation of spleen lymphocytes with histamine for 24 hr induces suppressor cells which inhibit the response to PHA, but not to LPS, of syngeneic lymphocytes in a coculture system, and which are radiosensitive. The role of PHA as a second stimulus of histamine-induced suppressor cells, and the relation between these cells and PHA or Con A-induced suppressor cells, are discussed.     

The role of Ia molecules in the activation of T lymphocytes. II. Ia-restricted recognition of allo K/D antigens is required for class I MHC-stimulated mixed lymphocyte responses

The role of Ia molecules in the T cell proliferative response to class I (H2K/D) MHC alloantigens was examined. Proliferation in response to allo-K/D antigenic stimulation, but not to allo-Ia, was markedly inhibited by the addition of monoclonal anti-responder Ia antibodies to cultures in the absence of C. This anti-Ia blocking was observed in responses against both allelic and mutant class I antigens. Partial blocking was observed by using an anti-I-A or anti-I-E monoclonal antibody alone, whereas marked inhibition was seen with these two reagents together when the proliferating cells derived from a responder strain expressing both IA and IE gene products. Syngeneic Ia molecules appear to function as restriction elements, because they are required even in the presence of a source of exogenous second signal, phorbol myristic acetate or IL 1. The K/D-specific response required a responding cell that bears both Lyt-1 and -2 antigens, whereas responses generated to alloantigenic differences, including the I region, require only an Ly-1+ cell. The implications of these data with respect to the repertoire of the alloreactive proliferating T cell and the expression of the Lyt-2 antigen by such cells are discussed.     

Class IA phosphoinositide 3-kinase modulates basal lymphocyte motility in the lymph node

Recruitment of PI3K to the cell membrane is an indispensable step in normal lymphocyte proliferation and activation. In this study we identify PI3K as an important signaling molecule for maintaining basal T and B lymphocyte motility and homing in the intact lymph node. Pharmacological inhibition of PI3K catalytic isoforms exerted broad effects on basal lymphocyte motility, including changes in homing kinetics, localization of B cells within the lymph node, and reduced cell velocities. Lymphocytes deficient in either or both of the class IA PI3K regulatory subunits p85alpha and p85beta also exhibited reduced velocities, with the magnitude of reduction depending upon both cell type and isoform specificity. B cells deficient in p85alpha exhibited gross morphological abnormalities that were not evident in cells treated with a PI3K inhibitor. Our results show, for the first time, that class IA PI3Ks play an important role in regulating basal lymphocyte motility and that p85alpha regulatory subunit expression is required to maintain B cell morphology in a manner independent of PI3K catalytic function. Moreover, we demonstrate distinct roles for catalytic domain function and class IA PI3K regulatory domain activity in lymphocyte motility, homing, and homeostatic localization of mature resting B cells.     

Fractionation of lymphocyte subpopulations which regulate mixed lymphocyte reactions.

Four days after injection of allogeneic lymphocytes BALB/c splenic T cells suppress proliferation of syngeneic cells in mixed lymphocyte reactions (MLR). Conversely, lymph node cells from the same mice amplify MLR responses. To further characterize these functional subpopulations, alloantigen-primed lymphocyte suspensions from both organs were fractionated by velocity sedimentation at unit-gravity. After fractionation MLR suppressor cells from spleens localized exclusively in rapidlly sedimenting fractions of large cells. MLR suppressor activity of cells from these fractions, as well as that of unfractionated spleen cell suspensions, was abolished by treatment with anti-Thy-1.2 serum and complement. Spleen cell fractions of similar sedimentation velocity also secreted a soluble MLR suppressor into culture supernatants. Although inhibitory of MLR, spleen cells of rapid sedimentation velocity did not suppress responses to T cell mitogens. In marked contrast with the effects of spleen cells, large 4-day-alloantigen-primed lymph node cells had no suppressive activity in MLR. MLR amplifier cells of uncertain derivation were found in fractions of medium sedimentation velocity from both spleens and lymph nodes. Fractionation of alloantigen-primed lymph node cell suspensions did reveal, however, a subpopulation of small cells with MLR suppressor acitivty which was unaffected by treatment with anti-Thy-1 serum and complement. The data thus indicate that large alloantigen-activated lymphocytes are not intrinsically suppressive nor are cells which suppress MLR necessarily large. We consequently conclude that regulation of MLR responses by alloantigen-primed lymphocytes involves a complex interaction between distinct functional subpopulations of cells which are separable both by physical and biologic properties.     

Control of mitogen-induced transformation: characterization of a splenic suppressor cell and its mode of action.

The present study demonstrates that mouse spleen cells contain a population of glass wool adherent T lymphocytes which exhibit the capacity to suppress non-glass adherent lymphocyte responses to mitogens. These suppressor cells are stimulated by both low and high doses of PHA¹ and high doses of con A. The suppressor cell effect is observed when UNA, but not RNA or protein synthesis, is studied. This glass-adherent suppressor cell population is characterized as being the primary DNA synthesizing cells during the early (0–8 hr) stages of culture. Suppression still occurs when the suppressor cells are treated with mitomycin C, actinomycin D or cycloheximide. This implies that new macromolecular synthesis may not be required for suppression to occur. Suppression is blocked by inhibiting synthesis of prostaglandin and is mimicked by Bu₂cAMP. This suggests that mitogen activated suppressor cells regulate T cell responses via production of prostaglandin which modulates the concentration of intracellular cyclic nucleotide levels.     

The control of autoreactivity. I. Lack of autoreactivity in murine spleens is due to concomitant presence of suppressor and autocytotoxic lymphocytes.

To determine if autocytotoxic lymphocytes were naturally occurring in murine spleens, C57BL/6 spleen cells were fractionated on discontinuous BSA gradients. Autocytotoxicity was assessed in vitro (cytotoxicity of C57BL/6 fibroblasts) and in vivo (splenomegaly and popliteal node enlargement in C57BL/6 mice). A medium density subpopulation of lymphocytes was shown to be autocytotoxic and to be similar to autoreactive lymphocytes produced by the in vitro "sensitization" of splenic lymphocytes on syngeneic fibroblasts monolayers. The naturally occurring autocytotoxic lymphocytes express no detectable theta antigen, did not adhere to nylon, but did have an Fc receptor. In recombination experiments, BSA-fractionated lymphocytes were incubated with autocytotoxic and "sensitized" lymphocytes. A light density subpopulation was shown to suppress both autoreactive lymphocyte subpopulations at a 1:50 ratio. The suppressor cells were nylon nonadherent T lymphocytes. The lack of autoreactivity of unfractionated murine spleen cells is due to the concomitant presence of autocytotoxic and suppressor lymphocytes. If suppressor lymphocytes are selectively removed in vitro, the reactivity of autocytotoxic lymphocytes can be detected.     

Characterization of granuloma T lymphocyte function from Schistosoma mansoni-infected mice

This study was undertaken to characterize and compare T lymphocyte function from the vigorous and modulated liver granulomas of Schistosoma mansoni-infected mice. Although both types of lesion contained equal percentages of T lymphocytes, the T cell subset distribution was different. For vigorous lesions, the ratio of helper/effector to suppressor/cytotoxic T cells was 2 to 3:1. For modulated lesions the ratio was lower (1:1). Differences in the phenotypic profiles of vigorous and modulated granuloma (Gr) T cells were reflected in their functional activity. Vigorous Gr T cells were more active in lymphoproliferation, IL-2 production, and granuloma formation than those from modulated lesions. Moreover, modulated Gr T cells suppressed the functional activity of vigorous Gr T cells in a dose-dependent manner. The selective depletion of T cell subsets showed that phenotypically, the Gr delayed-hypersensitivity T cell is L3T4+, Lyt-1+ whereas the Gr Ts cell is an Lyt-2+ lymphocyte. Both of these T cell subsets are present in vigorous and modulated lesions. During acute infection, delayed-hypersensitivity T cell lymphocyte functions predominate, whereas Ts lymphocyte functions appear to prevail during chronic infection.     

The double cascade of lymphoid proliferation: current challenges and problems areas

Two largely but not entirely separate cascades of proliferation and differentiation are involved in immunity. First, processes that are mainly independent of the entry of antigen into the body generate the two types of lymphocytes, T cells and B cells. This lymphoneogenesis proceeds in the thymus and the bone marrow, respectively. It creates families and subfamilies of nondividing cells that do nothing but patrol the body until antigen enters. Each lymphocyte set represents a repertoire of recognition units preequipped with receptors for antigen, and each individual lymphocyte carries its own particular specificity as a result of a somatic rearrangement of genes. When an antigenic stimulus is given, the second and antigen-dependent wave of proliferation and differentiation occurs. This involves clonal selection of particular lymphocytes within the repertoire with specificity for the antigen, and the generation of both immunologic effector cells and memory cells. This second cellular cascade takes place chiefly in the secondary lymphoid tissues, e.g., lymph nodes or spleen. The developing immune system learns to discriminate self from not-self. The paper outlines the chief mechanisms operative in immunologic tolerance and also briefly addresses the fact that T lymphocytes must learn to "see" antigens in association with a "self" major-histocompatibility-complex antigen. Both proliferative cascades depend on intercellular interactions, but much more is known about those operative in antigen-driven lymphocyte activation. Here there is a cyclical process in which antigen-trapping cells stimulate helper/inducer T cells, which in turn stimulate cytotoxic/suppressor T cells or B cells. Some T-cell products can augment the antigen-trapping cells' inductive role.(ABSTRACT TRUNCATED AT 250 WORDS)