The avian model in the study of tolerance to self.
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Mechanisms of tolerance to self.
Several mechanisms exist to prevent lymphocytes from reacting against self-antigens. As T cells develop in the thymus and express antigen-specific receptors, those with high-affinity to self-antigens existing within the thymus are deleted. Low-affinity self-reactive T cells and T cells with receptors against antigens not represented intrathymically will mature and join the peripheral T cell pool. They may either ignore self-antigens expressed by tissues unable to activate T cells through a lack of the appropriate costimulator signals, or they may, under certain conditions, be deleted or rendered anergic and unable to respond. Likewise, B cells that express surface Ig receptors with high binding affinity to membrane-bound self-antigens present in the bone marrow will be rescued by receptor editing or will be deleted, whereas those of lower affinity will migrate to the periphery in either an anergic or indifferent state depending on the degree of receptor engagement by antigen. Once there, their ultimate fate is determined by the availability of T cell help.
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Positive and negative selection of T cell repertoires during differentiation in allogeneic bone marrow chimeras.
T cells acquire immune functions during expansion and differentiation in the thymus. Mature T cells respond to peptide antigens (Ag) derived from foreign proteins when these peptide Ag are presented on the self major histocompatibility complex (MHC) molecules but not on allo-MHC. This is termed self-MHC restriction. On the other hand, T cells do not induce aggressive responses to self Ag (self-tolerance). Self-MHC restriction and self-tolerance are not genetically determined but acquired a posteriori by positive and negative selection in the thymus in harmony with the functional maturation. Allogeneic bone marrow (BM) chimera systems have been a useful strategy to elucidate mechanisms underlying positive and negative selection. In this communication, the contribution of BM chimera systems to the investigation of the world of T-ology is discussed.
Amino Acid Sequence↗
Proinsulin: a unique autoantigen triggering autoimmune diabetes.
In healthy individuals the immune system does not react aggressively toward host cells, a phenomenon defined as self tolerance. If self tolerance is broken autoimmune disease can develop, during which autoreactive lymphocytes are directed to a variety of autoantigenic epitopes. However, researchers have yet to determine whether immune responses to multiple autoantigens develop independently of each other or are the result of the response "spreading" from one autoantigen to another. In a study of NOD mice in this issue of the JCI, Krishnamurthy et al. show that the autoreactive T cell response to the autoantigen proinsulin lies upstream of that to islet-specific glucose-6-phosphatase catalytic subunit-related protein, suggesting that the pathogenic autoimmune response to proinsulin subsequently spreads to other antigens (see the related article beginning on page 3258). These data support the current view that this pancreatic beta cell hormone is the first autoantigen targeted by the immune response in autoimmune diabetes.
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B cell tolerance to self in systemic autoimmunity.
After a century of research and despite intensive scrutiny, the origin of autoantibody production remains an enigma. Recently, the essential role of B cells in promoting systemic autoimmunity in mice seems more important than previously thought: self-reactive B cells can be subject to positive selection and a deficiency in serum IgM predisposes to the development of IgG antibodies to autoantigens. Studies of the B cell repertoire expressed in systemic autoimmune diseases have provided important clues. In human lupus, quantitation of this repertoire reveals the presence of an expansion of IgG clonotypes that impart reactivity with disease-related autoantigens. The nucleotide sequences of autoantibodies derived from these patients and expressing nephritogenic idiotopes (present in immune complexes and renal eluates of subjects with active disease) show features of diversification with a high rate of replacement/silent mutations and clustering of the mutations in the hypervariable regions, suggesting than an antigen-driven process plays a role in the generation of pathogenic autoantibodies. Currently, the contributions of apoptosis and of cell receptor signaling to this triggering are being appreciated. Pursuing these and related issues will have an important impact on autoimmune research.
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Apoptosis and transplantation tolerance.
Self-tolerance is maintained by several mechanisms including deletion (via apoptosis) and regulation. Acquired tolerance to allogeneic tissues and organs exploits similar strategies. One key difference between alloantigens and peptide antigens is the enormous number of T cells that are alloreactive. Accumulating evidence suggests that in the face of this large mass of potentially graft-destructive T cells, tolerance requires an initial wave of deletion. This creates a more level playing field in which a smaller number of regulatory T cells can then act to maintain an established tolerant state. Deletion of alloreactive T cells by apoptosis actively promotes immunoregulation as well, by interfering with proinflammatory maturation of antigen presenting cells. This article reviews the immune response to alloantigens, the development and use of both necrotic and apoptotic means of cell death during the evolution of the immune response, and the likely role and mechanisms by which apoptosis promotes, and may even be required for, transplantation tolerance.
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AIRE-1 (autoimmune regulator type 1) as a regulator of the thymic induction of negative selection.
The monogenic autoimmune syndrome, APS-1 (autoimmune polyglandular syndrome type 1), is characterized by the loss of self-tolerance to multiple organs. Although mutations in the AIRE (autoimmune regulator) gene are responsible for the APS-1, the function of AIRE is not known. AIRE may determine thymic induction of tolerance to self-antigens in multiple organs. To study the function of AIRE in induction of self-tolerance, an in vitro negative selection system was made using 10(6) DO11.10 TCR transgenic thymocytes, 10(5) antigen-presenting cells (APC), and the different constructs of ovalbumin (OVA). In this system, the addition of the immunodominant epitopes of OVA peptide, the antigenic ligand for the DO11.10, made the thymocytes apoptotic and negatively selected. Overexpression of the AIRE gene in APC using retroviral transduction did not cause more thymocytes to become apoptotic. However, the suppression of the expression of AIRE in APC using the dominant-negative gene made the recovery rates of the thymocytes higher than those with the expression of LacZ as a control, and consequently inducing loss of self-tolerance. From these studies, it might be possible to suggest that the AIRE gene might regulate thymic induction of the negative selection process. The target genes for transcriptional regulation by AIRE have been investigated to study the influence of AIRE expression on other proteins in antigen presentation. The expression level of B7.1 was higher in APC expressing the dominant-negative form of AIRE. The target gene regulated by AIRE in transcription will be screened using cDNA microarray.
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Disruption of T cell tolerance by directing a self antigen to macrophage-specific scavenger receptors.
Breakdown of immune self tolerance is speculated to cause autoimmune diseases, but most studies on tolerance use foreign molecules as targets. In this study, we show another approach using delivery of a maleylated self protein to macrophage-specific scavenger receptors. Mice generate Abs against the maleylated form of a ubiquitous self Ag, mouse serum albumin (MSA), although native MSA is nonimmunogenic. This generation of anti-maleyl MSA Abs depends on binding of maleyl MSA to scavenger receptors in vivo, since coinjection of a serologically unrelated scavenger receptor ligand inhibits it, suggesting that the Ab response is T cell dependent. Spleen cells as well as nylon adherence-purified splenic T cells from maleyl MSA-immune mice proliferate in response to both maleyl MSA and MSA; this response is blocked by anti-MHC class II mAbs, and the autoimmune cells can recognize at least five 15-mer peptides from the MSA sequence, establishing that T cell tolerance to MSA has been broken in these mice. Maleyl MSA and MSA are recognized equally well, provided the scavenger receptor-specific delivery of maleyl MSA is blocked during stimulation in vitro, indicating that maleyl MSA-specific non-self peptides are unlikely to play a major role in the observed disruption of T cell tolerance. Thus, delivery of some self molecules to scavenger receptors may lead to disruption of immune tolerance. These results are relevant to mechanisms of immune tolerance and the etiopathogenesis of autoimmunity.
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Expansion of neonatal tolerance to self in adult life: I. The role of a bacterial adjuvant in tolerance spread.
T cell neonatal tolerance to self evolves perturbation of the Th1/Th2 balance towards Th2-type self-specific T cells. In the current study we have demonstrated that a tolerant state could be extended to another encephalitogenic determinant only if the neonatally tolerizing determinant was co-administered in adult life with an emulsion of Mycobacterium tuberculosis (i.e. complete Freund's adjuvant). The mechanisms underlying tolerance elicitation and expansion were then explored by an in vitro system in which indirect suppression could be measured. Addition of a tolerizing epitope to splenic T cells from neonatally tolerized animals induced a marked suppression of the anti-MT response. This response could be restored by neutralizing antibodies to IL-4. In contrast, the neutralizing antibodies to IL-4 had no affect on the response of these cells to the tolerizing determinant. These findings are highly significant not only because they explore the important role of microbial antigens in neonatal tolerance, but also because they distinguish, for the first time, between tolerizing and tolerized T cells.
Aging↗
Immunologic tolerance: development and disruption.
Loss of tolerance to self-antigens is thought to have a role in a variety of common diseases. Studies in animal models of such diseases as systemic lupus erythematosus have provided new insights into how self-tolerance is broken or bypassed and how it may be restored. These and other experiments also are clarifying how self-tolerance is normally established; the T lymphocyte appears to be the dominant player.
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Autosensitization in vitro.
Autosensitization of rat or mouse lymphoid cells against syngeneic fibroblast antigens was induced in cell culture. Rat lymphoid cells autosensitized by this method were able to produce immunospecific lysis of syngeneic target fibroblasts in vitro or GvH reactions in newborn rats. Autosensitized mouse spleen cells mediated similar GvH reactions when injected into newborn mice. The nature of the system used to induce immunity in vitro appears to argue against the possibility that lymphocytes capable of reacting against self-antigens could arise by mutation in cell culture. Hence, it is likely that cells potentially reactive against self-antigens preexisted in the lymphoid cell donors. The ability of autosensitized cells to mediate immune reactions in vivo suggests that the immunogenic self-antigens present on sensitizing fibroblasts also were accessible in the intact animals. Loss of natural self-tolerance in vitro, therefore, can be explained most simply by the existence of lymphocytes which are reversibly tolerant to self. Hence, ontogenic elimination of potentially self-reactive cells may not be the only basis for natural tolerance. Regulatory mechanisms, such as antigen excess, may have to function in vivo to prevent differentiation of self-tolerant lymphocytes. These regulatory mechanisms appear to be annulled in the cell-culture system. The present system thus may offer a new approach to studies of tolerance and regulation of cellular immunity.
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The T-cell repertoire is heavily influenced by tolerance to polymorphic self-antigens.
T cells with V beta 3+ alpha beta receptors are deleted by self-tolerance in mice with particular major histocompatibility complex/self-antigen combinations. This also occurs for other V beta elements. Polymorphism in the major histocompatibility complex and/or the self-antigens that cause massive deletion of T cells using particular V beta elements may be maintained by the need to balance the advantage of a diverse T-cell repertoire against the potential involvement of those elements in autoimmune disease.
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Biology of T memory type 1 cells.
Engagement of inhibitory natural killer (NK) cell receptors for MHC class I molecules (NKR) can impair NK-cell activation programs. Inhibitory NKR thus confer to NK cells the capacity to discriminate between MHC class I+ and MHC class I- target cells, and are therefore involved in the control of NK-cell tolerance to self, as well as in the elimination of MHC class I- distressed cells by NK cells. In human and mouse, a subset of alphabeta T cells also express inhibitory NKR at their surface, but the biological function of inhibitory NKR on T cells remains to be precisely elucidated. We refer to these cells as T memory type 1 (Tm1) cells, and review here the phenotypic and functional features of this subset of memory-phenotype CD8+ alphabeta T cells. In vitro studies suggest that inhibitory NKR are involved in the peripheral control of T-cell self-tolerance. In vitro and in vivo analysis have revealed a novel biological function for inhibitory NKR when expressed on T cells. Indeed, engagement of inhibitory NKR on T cells provides them with survival signals against activation-induced cell death. Thus, sensing of self-MHC class I molecules by inhibitory NKR displayed on alphabeta T cells leads to the in vivo accumulation of Tm1 cells.
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Activation-threshold tuning in an affinity model for the T-cell repertoire.
Naive T cells respond to peptides from foreign proteins and remain tolerant to self peptides from endogenous proteins. It has been suggested that self tolerance comes about by a 'tuning' mechanism, i.e. by increasing the T-cell activation threshold upon interaction with self peptides. Here, we explore how such an adaptive mechanism of T-cell tolerance would influence the reactivity of the T-cell repertoire to foreign peptides. We develop a computer simulation model in which T cells are tolerized by increasing their activation-threshold dependent on the affinity with which they see self peptides presented in the thymus. Thus, different T cells acquire different activation thresholds (i.e. different cross-reactivities). In previous mathematical models, T-cell tolerance was deletional and based on a fixed cross-reactivity parameter, which was assumed to have evolved to an optimal value. Comparing these two different tolerance-induction mechanisms, we found that the tuning model performs somewhat better than an optimized deletion model in terms of the reactivity to foreign antigens. Thus, evolutionary optimization of clonal cross-reactivity is not required. A straightforward extension of the tuning model is to delete T-cell clones that obtain a too high activation threshold, and to replace these by new clones. The reactivity of the immune repertoires of such a replacement model is enchanced compared with the basic tuning model. These results demonstrate that activation-threshold tuning is a functional mechanism for self tolerance induction.
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Investigation of a mechanism for accelerated breakdown of immune tolerance to the primary biliary cirrhosis-associated autoantigen, pyruvate dehydrogenase complex.
Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by autoreactive T- and B-cell responses to the highly conserved enzyme pyruvate dehydrogenase complex (PDC). In this study we have examined the breakdown of T-cell tolerance to self-PDC using a mouse model. Female SJL/J mice were sensitized intraperitoneally with foreign-PDC (bovine) and/or self-PDC (murine) in complete Freund's adjuvant, and serum, spleen, and liver tissue was taken 8 weeks later. Animals sensitized with foreign-PDC produced IgG antibodies that were reactive with both foreign and self-PDC, but splenic T cells from these animals only responded to stimulation with foreign PDC. Sensitization with self-PDC elicited neither antibodies nor reactive T cells. Significantly, cosensitization with mixed self-PDC and foreign-PDC resulted in a full breakdown of self-tolerance, with generation of both antibody and T-cell responses to self-PDC of the type seen exclusively in human PBC patients. Mild bile duct lesions deficient in CD8(+) T cells were seen 8 weeks after sensitization with either foreign or self-PDC. However, after sensitization with mixed self-PDC and foreign-PDC, these lesions were significantly larger and heavily infiltrated by CD8(+) T cells. Liver-infiltrating T cells derived from the self-PDC and foreign-PDC cosensitized but not from control animals showed reactivity with self-PDC, suggesting a possible role for autoreactive PDC-specific T-cell responses in the pathogenesis of the observed histologic changes. It is likely that B-cell cross-reactivity between foreign and self-PDC enhances the potential for breakdown of T-cell self-tolerance by allowing efficient presentation of self-antigens in the inoculum. This model may provide a useful system for investigating the etiology and treatment of PBC.
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Future approaches to factor VIII inhibitor therapy.
Future progress in our ability to treat acquired factor VIII (FVIII) inhibitors must be based on advances in knowledge of both the FVIII molecule and the nature of the human immune response. New therapeutic approaches to patients with acquired FVIII inhibition likely will emphasize modifications of the immune response. This concept holds considerable promise, because studies have characterized the critical steps leading to tolerance of self-antigens. Development of FVIII inhibitors represents a loss of self-tolerance, which any successful therapy must restore. Conceivably, restoration of self-tolerance can be accomplished in many ways: prevention of antigen binding to helper T lymphocytes, deletion of self-antigen-reactive T cells, inhibition of major histocompatibility complex (MHC) recognition, or enhancement of the antigen-specific suppressor T lymphocyte population. Recent data have demonstrated that highly specific methods can suppress ongoing immune responses against defined autoantigens. Antibodies that inhibit T-cell activation, peptides that block self-antigen binding, and antibodies that inhibit MHC recognition all have been successful in modifying experimentally induced autoimmune diseases. Whether any of these immunotherapeutic approaches will be effective in the treatment of acquired FVIII inhibition remains to be determined. Until data from animal model systems establish the feasibility of immune intervention, scrutiny of other new therapeutic approaches to patients with spontaneous inhibitors will continue to be important. Administration of FVIII-bypassing procoagulant proteins shows promise, as does removal of inhibitors by affinity reagents, such as FVIII peptides containing relevant epitopes (antigenic sites). Farther on the horizon is development of recombinant FVIII molecules so modified as to remove antigenic determinants while preserving procoagulant function. Articles in this supplement summarize several avenues for treatment of patients with acquired FVIII inhibitors. Alternatives include treatment with sufficient human or porcine FVIII to offset inhibitors, use of materials that reestablish hemostasis even though FVIII levels are not increased (the so-called FVIII-bypassing agents), manipulation of immune responses through physical depletion of inhibitor by plasmapheresis or affinity chromatography, and administration of intravenous immunoglobulin or immunosuppressive cytotoxic drugs. Thus, the heterogeneous clinical presentation is paralleled by the wide range of available therapeutic approaches.
Autoantibodies↗
Role of the H-2 complex in the induction of T cell tolerance to self minor histocompatibility antigens.
The present study has utilized cytotoxic T lymphocyte (CTL) responses specific for minor histocompatibility (minor H) antigens as an experimental approach to determining whether recognition of self MHC determinants is involved in the induction of T cell tolerance to self antigens. It was observed that C3H.SW splenic T cells from C3H.SW leads to B10 X B10.BR radiation bone marrow chimeras contained CTL precursors (pCTL) reactive against self C3H minor H antigens + H-2k but were tolerant to self C3H minor H antigens + H-2b. Precursor CTL with the reciprocal reactivity pattern were observed for C3H leads to B10 X B10.BR chimeras. In addition, it was observed that C3H.SW thymocytes from C3H.SW leads to B10 X B10.BR chimeras could generate minor H-specific CTL responses and were reactive against self C3H minor H antigens + H-2k, but were tolerant to self C3H minor H antigens + H-2b. Thus, the present study demonstrates that for peripheral and intrathymic T cell populations at least a component of T cell tolerance to self antigens is restricted by products of the MHC.
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The immune system victorious: selective preservation of self.
How the body successfully distinguishes its own tissue cells from those that are foreign and genetically nonidentical to it has been a focus of much research. Clonal deletion maintains that immune system cells with the potential to injure self constituents are eliminated during development, thereby neutralizing their capacity to induce self injury. Selected self-reactive maturing T cell clones undergo deletion in the thymus. A two-step selection process affects immature T cells that enter the thymus. Positive selection makes certain that all surviving cells are able to identify major histocompatibility complex (MHC) proteins present on all body cells. These MHC proteins interact with antigens and present them to T lymphocytes. Negative selection is essential for self-tolerance. It eliminates potentially injurious self-reactive T cells by placing them in contact with a mixture of self antigens in the thymus. Clonal anergy might act together with clonal deletion to maintain self tolerance. Self-reactive T cells in the blood of healthy subjects could represent cells whose affinities for antigen are too weak to initiate an immunologic disease. The fate of T cells reacting to a specific antigen has been traced in transgenic mice. Class I MHC molecules present peptides manufactured within the cell, whereas class II MHC molecules present peptides from extracellular proteins. Interaction of a T cell receptor with its homologous antigen associated with MHC molecules leads to proliferation of that T cell in the presence of costimulatory signals. Investigations elucidating the role of T cell receptors, MHC molecules and antigen peptides in self-nonself discrimination are discussed. The article concludes with an introductory summary of the remaining articles in the issue that address selected topics in self-nonself discrimination.
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