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PubMed1992

Peripheral T cell tolerance.

The most efficient way to ensure self-tolerance in the T-cell repertoire is by intrathymic deletion of self-reactive clones. Antigens not present intrathymically may, however, influence the peripheral T-cell pool in various ways. The may of course activate T cells, provided that these have the correct specificity and affinity and that the antigens are presented in sufficient amounts on professional antigen-presenting cells. They may be ignored by T cells if some of these conditions are not met. In some forms, the antigen may be toleragenic for mature T cells. If the antigens persist in an immunogenic form, unresponsiveness may eventually be imposed as the end result of a powerful immune response. Extrathymic self-antigenic components are generally encountered early in development, and the way in which these influence peripheral T lymphocytes has been studied by transgenic technology. They may be ignored by T cells if they are sequestered from the immune system, or if they are present in low amounts or on nonprofessional antigen-presenting cells which lack the appropriate accessory molecules or signals needed to activate the relevant T-cell subset. On the other hand, some of these self-antigens readily induce anergy in peripheral T cells, which may or may not involve downregulation of antigen receptors and coreceptors. Tolerance in the T-cell repertoire is therefore achieved not only by intrathymic deletion of self-reactive clones but also by several postthymic mechanisms.

Animals↗
PubMed1997

Different nuclear signals are activated by the B cell receptor during positive versus negative signaling.

It is not known how immunogenic versus tolerogenic cellular responses are signaled by receptors such as the B cell antigen receptor (BCR). Here we compare BCR signaling in naive cells that respond positively to foreign antigen and self-tolerant cells that respond negatively to self-antigen. In naive cells, foreign antigen triggered a large biphasic calcium response and activated nuclear signals through NF-AT, NF-kappa B, JNK, and ERK/pp90rsk. In tolerant B cells, self-antigen stimulated low calcium oscillations and activated NF-AT and ERK/pp90rsk but not NF-kappa B or JNK. Self-reactive B cells lacking the phosphatase CD45 did not exhibit calcium oscillations or ERK/pp90rsk activation, nor did they repond negatively to self-antigen. These data reveal striking biochemical differences in BCR signaling to the nucleus during positive selection by foreign antigens and negative selection by self-antigens.

Animals↗
PubMed1987

Immunological discrimination between self and non-self by precursor depletion and memory accumulation.

We study processes by which T-lymphocytes "learn" to discriminate "self" from "non-self". We show that intrinsic features of the T cell activation and proliferation process are sufficient to tolerize (self) reactive T-lymphocyte clones. Self vs non-self discrimination therefore develops without any down-regulatory (e.g. suppressive) interactions. T-lymphocyte clones will expand by proliferation only if the IL2 concentration is high enough to induce a proliferation rate larger than the rate of cell decay. This concentration is the proliferation threshold. Because effector T cells are short-lived the proliferation threshold must be quite high. Such high numbers of cells producing IL2 are achieved only when sufficient (memory) precursors are activated. Self and non-self antigens differ with respect the number of (memory) precursor cells they accumulate, as a result of two processes, i.e. precursor depletion and memory accumulation, and can thus be discriminated. Precursor depletion: the dynamics of long-lived precursors can cause tolerization. In neonatal circumstances precursor influx is still low, newborn cells reacting with self antigens are immediately activated, generating (few), i.e. fewer than the proliferation threshold, effectors that decay rapidly. Thus total lymphocyte numbers remain low, yielding self tolerance. Conversely, large doses of similar antigens introduced in mature systems push "their" lymphocyte clone over the proliferation threshold because a large (accumulated) precursor population is rapidly activated. Small doses are however low zone tolerized. Memory accumulation: peripheral T-lymphocyte populations in fact consist of a mixture of virgin precursors and memory cells. If the formation process of (long-lived) memory cells is taken into account and virgin precursors are made short-lived, the proliferation threshold again accounts for self non-self discrimination. Memory cells accumulate when antigenic restimulation is low; it is low when the antigen concentration and/or the antigen affinity is low. Therefore self antigens, which are present in relatively high concentrations, fail to accumulate high affinity memory cells, and are hence tolerated. Memory cells crossreacting to self antigens with low affinity, however accumulate neonatally, pushing those clones over the proliferation threshold whenever "their" high affinity antigen enters the immune system. Thus the model generates differences in the antigenicity (i.e. memory precursor frequency) of self and non-self.(ABSTRACT TRUNCATED AT 400 WORDS)

Antigens↗
PubMed1996

Balancing immunity and tolerance: deleting and tuning lymphocyte repertoires.

Immunological self-tolerance is ensured by eliminating or inhibiting self-reactive lymphocyte clones, creating physical or functional holes in the B- and T-lymphocyte antigen receptor repertoires. The nature and size of these gaps in our immune defenses must be balanced against the necessity of mounting rapid immune responses to an everchanging array of foreign pathogens. To achieve this balance, only a fraction of particularly hazardous self-reactive clones appears to be physically eliminated from the repertoire in a manner that fully prevents their recruitment into an antimicrobial immune response. Many self-reactive cells are retained with a variety of conditional and potentially flexible restraints: (i) their ability to be triggered by antigen is diminished by mechanisms that tune down signaling by their antigen receptors, (ii) their ability to carry out inflammatory effector functions can be inhibited, and (iii) their capacity to migrate and persist is constrained. This balance between tolerance and immunity can be shifted, altering susceptibility to autoimmune disease and to infection by genetic or environmental differences either in the way antigens are presented, in the tuning molecules that adjust triggering set points for lymphocyte responses to antigen, or in the effector molecules that eliminate, retain, or expand particular clones.

Animals↗
PubMed2003

CD200 is a novel p53-target gene involved in apoptosis-associated immune tolerance.

During apoptotic cell death, biochemical processes modify self-proteins and create potential autoantigens. To maintain self-tolerance in the face of natural cell turnover, the immune system must prevent or control responses to apoptosis-associated autoantigens or risk autoimmunity. The molecular mechanisms governing this process remain largely unknown. Here, we show that expression of the immunoregulatory protein CD200 increases as murine dendritic cells (DCs) undergo apoptosis. We define CD200 as a p53-target gene and identify both p53- and caspase-dependent pathways that control CD200 expression during apoptosis. CD200 expression on apoptotic DCs diminishes proinflammatory cytokine production in response to self-antigens in vitro and is required for UVB-mediated tolerance to haptenated self-proteins in vivo. Up-regulation of CD200 may represent a novel mechanism, whereby immune reactivity to apoptosis-associated self-antigens is suppressed under steady state conditions.

Animals↗
PubMed1997

The role of T cells in the regulation of B cell tolerance.

The study of conventional models of B cell tolerance has suggested that self-tolerance is imposed on B cells at an early stage in their development due to a peculiar sensitivity of immature B cells to tolerance induction. While this concept accounts for some aspects of central B cell tolerance, it is inconsistent with recent reports of tolerance induction in mature splenic B cells from immunoglobulin transgenic mice. We present an alternative model, the hierarchical model (Aust. N. Z. J. Med. 25, 761-767, 1995), in which regulation of naive B cell reactivity is a function of antigen signal strength and availability of T cell help, but is independent of B cell maturation stage. In turn, the development of tolerance or memory in the T cell compartment is dependent on a combination of antigen-MHC recognition by T cells and antigen-nonspecific signalling by antigen-presenting cells. Using a transgenic model of T-B collaboration, we have shown that both immature and mature self-reactive B cells can be rescued and induced to secrete auto-antibody if the B cell determinant is linked to a carrier protein bearing a foreign T cell determinant.

Animals↗
PubMed1989

The influence of self-MHC and non-MHC antigens on the selection of an antigen-specific T cell receptor repertoire.

We have examined the influence of self-Ag on TCR expression and specificity in the immune response to the Ag pigeon cytochrome c. Previous work has shown that most Ek-restricted cytochrome c-specific T cells from B10 background mice express TCR alpha beta-heterodimers encoded by V beta 3 and V alpha 11 genes, but that T cells expressing V beta 3 proteins are eliminated due to self-tolerance in Mls-2a mouse strains. Thus, EK-restricted cytochrome c-specific T cells from Mls-2a mice fail to express any V beta 3. In the current study the influence of self-MHC and non-MHC Ag on TCR usage in the immune response to cytochrome c was further examined. First, it was demonstrated that the absence of V beta 3 expression in Mls-2a mice does not alter Ir gene function. Specifically, Mls-2a/Eb haplotype V beta 3- [C3H.SW x B10.A(5R)]F1 mice were high responders to cytochrome c despite the fact that previous structure function analyses have shown a very close correlation between Eb-restricted cytochrome c recognition and V beta 3 expression. This demonstration of the plasticity of TCR expression suggests that relatively few Ir gene defects result from tolerance induced by self-Ag. We also examined differences in V alpha 11 expression among cytochrome c-specific T cells from various H-2k haplotype mouse strains. In particular, the low level of expression of V alpha 11 in cytochrome c-specific T cells from C57BR (H-2k) mice was shown not to be due to self-tolerance. Rather, evidence for limited strain polymorphism of V alpha 11 genes, plus the fact that cytochrome c-specific T cells from F1 hybrids between H-2k, Mls-2b identical C57BR and B10.BR mice express high levels of V alpha 11, suggested the possibility that the variable V alpha 11 usage in the cytochrome c-specific responses of these two strains reflected differences in positive selection during ontogeny by non-MHC non-Mls self-Ag.

Animals↗
PubMed1992

A transgenic window on peripheral T cell tolerance.

There is convincing evidence for the imposition of self-tolerance by means of the clonal deletion of self-reactive T cells within the thymus. Since not all self components may be encountered there, the question must be asked whether tolerance can occur post-thymically. To test this, we have used transgenic technology to direct expression of a 'non-self' gene, H-2Kb, to the insulin-producing beta cells of the pancreas in mice. These 'RIP-Kb' transgenic mice were specifically tolerant of H-2Kb-bearing skin grafts. To test the fate of potentially reactive H-2Kb-specific T cells in these tolerant mice, the RIP-Kb mice were mated to a second series of transgenic mice with rearranged T cell receptor (TCR) genes encoding an H-2Kb-specific TCR to produce 'double transgenic' offspring. The TCR was detectable by a clonotype-specific antibody. Although there was some evidence of intrathymic deletion of those T cells that expressed the highest density of the H-2Kb-specific TCR, lower density cells were present in the periphery. These may have been either indifferent to the H-2Kb molecule expressed on the beta cells or functionally silenced by it. Further experiments are planned to determine which of these two situations exists.

Animals↗
PubMed1995

Role of viruses in the loss of tolerance to self-antigens and in autoimmune diseases.

The breaking of tolerance to self-antigens, involving the activation of self-reactive lymphocytes, is a critical event leading to autoimmune disease. The precise mechanisms by which this occurs are unknown, but among other etiological factors, viruses have been implicated. Recent results with animal models of insulin-dependent diabetes provide insight into how viruses induce autoimmune disease.

Animals↗
PubMed2006

Complement receptor 2, natural antibodies and innate immunity: Inter-relationships in B cell selection and activation.

Complement receptor type 2 (CR2) is a receptor that serves as an important interface between the complement system and adaptive immunity. Recent studies have shown that CR2 is also centrally involved in innate immunity, and one key area is the development of potentially pathogenic natural antibodies that target neo-epitopes revealed in ischemic tissue undergoing reperfusion. Mice lacking either total immunoglobulins or CR2 alone are protected from the development of ischemia-reperfusion injury, and this effect can be reversed by introducing CR2-sufficient B-1 cells or by transferring polyclonal natural IgM antibody from wild type mice as well as monoclonal antibodies that recognize phospholipids, DNA or non-muscle myosin. We will report at the XXI ICW an additional membrane-associated protein to which pathogenic IgM antibodies are directed. Whether B cells producing these natural antibodies are differentially selected in CR2-deficient mice is as yet not well understood, and the complement-related mechanism(s) whereby this differential repertoire selection process could occur have yet to be explored in any detail. In addition to this important role in innate immunity, CR2 can also act as a receptor for other components or activators of innate immunity. One such component is interferon-alpha, an anti-viral cytokine that binds CR2 and induces a component of its mRNA signature in B cells through this receptor. Other potential CR2 ligands are DNA and DNA-containing complexes such as chromatin. The biologic role of these CR2 interactions with interferon-alpha and DNA-containing complexes is not well understood, but may be important in the development of the autoimmune disease systemic lupus erythematosus that is characterized by enhanced interferon-alpha levels and loss of self tolerance to DNA-containing self antigens.

Animals↗
PubMed1996

Organ-specific disease provoked by systemic autoimmunity.

Rheumatoid arthritis (RA) is a chronic joint disease characterized by leukocyte invasion and synoviocyte activation followed by cartilage and bone destruction. Its etiology and pathogenesis are poorly understood. We describe a spontaneous mouse model of this syndrome, generated fortuitously by crossing a T cell receptor (TCR) transgenic line with the NOD strain. All offspring develop a joint disease highly reminiscent of RA in man. The trigger for the murine disorder is chance recognition of a NOD-derived major histocompatibility complex (MHC) class II molecule by the transgenic TCR; progression to arthritis involves CD4+ T, B, and probably myeloid cells. Thus, a joint-specific disease need not arise from response to a joint-specific antigen but can be precipitated by a breakdown in general mechanisms of self-tolerance resulting in systemic self-reactivity. We suggest that human RA develops by an analogous mechanism.

Alleles↗
PubMed2002

Interleukin-10 is crucial for maintenance but not for developmental induction of peripheral T cell tolerance.

To asses the requirement of interleukin (IL)-10 for peripheral CD4 T cell tolerance, the IL-10 knockout (KO) was introduced into a T cell receptor-transgenic mouse model (TCR1) specific for SV40 T antigen (Tag). IL-10-deficient TCR1-transgenic mice failed to establish antigen-specific T cell tolerance following sequential injections with Tag peptide. Nevertheless, IL-10 was not required for the establishment of CD4 T cell tolerance in double transgenic RT2/TCR1 mice in which Tag is expressed endogenously under control of the insulin promoter. However, in contrast to stable anergy in wild-type RT2/TCR1 mice, tolerant T cells in RT2/TCR1/Il-10KO mice could be driven into vigorous proliferation by exogenous antigenic stimulation in vivo. The observed reactivation of anergic T cell populations in IL-10-deficient mice was only seen after in vivo but not in vitro peptide priming, reflecting an important regulatory function of IL-10 in the context of the living organism. Taken together, these results demonstrate that IL-10 is required to maintain T cell tolerance following exposure to enhanced antigenic stimuli but is not essential for the induction of self-tolerance.

Animals↗
PubMed1989

Poor repertoire selection in symmetric idiotypic network models.

The selection of B and T cell repertoires is known to be influence by idiotypic interactions during early ontogeny. Early B cell clones are multi-specific, have numerous idiotypic interactions, produce IgM antibodies, and may constitute a separate cell lineage (characterised by the Ly1 or CD5 marker). Furthermore, because early B cells are self-reactive, self antigens should play a crucial role in the repertoire selection. Previously we developed a theoretical model of idiotypic B cell interactions. The model is based on a (symmetric) bell-shaped interaction function. The symmetry and the shape are a consequence of the process of receptor crosslinking. Assuming that early (i.e. IgM) B cell interactions are independent of helper T cell activation, we now apply this model to the problem of idiotypic repertoire selection. In the model the molecular structures of B cell receptors (i.e. of the idiotypes) and of self antigens are represented by random (bit)patterns. Interactions are based on complementary matches between these patterns. Therefore, the repertoire selection is brought about by stimulatory networks based upon complementary matches. These results show that the presence of a self antigen specifically shapes the B cell repertoire. The selection depends on the nature of the antigenic signal; we incorporate either stimulatory or inhibitory (i.e. tolerizing) self antigens. Clones stimulated by the self antigen tend to become aggressive in the network; tolerized self-reactive clones tend to become suppressed. Thus, idiotypic interactions play a facilitating role in self/non-self discrimination. However, since the idiotypic selection is only a tendency, the immune system should not rely on it. We next incorporate two classes of B cells. We call them the early, or "IgM", and the late, or "IgG", B cells (IgG B cells appear after the development of the IgM repertoire). IgG B cells may have only a few idiotypic interactions. We investigate whether the early IgM repertoire, which is (partly) selected by self antigen, influences the selection of the late IgG repertoire. It turns out that this influence can only be non-specific. Either we find a similar tendency in the IgG repertoire, or we find that the IgG repertoire influences the IgM repertoire non-specifically. Thus, despite the fact that this theoretical work readily confirms empirical results showing that the manipulation of early idiotypic interactions can have specific and long-lasting effects, the presupposed physiological role of these interactions, in terms of self-reactivity or repertoire selection, fails to develop in our models.

Animals↗
PubMed2005

Peripheral tolerance of CD8 T lymphocytes.

Whereas high-avidity recognition of peptide-MHC complexes by developing T cells in the thymus results in deletion and promotes self-tolerance, such recognition by mature T cells in the periphery results in activation and clonal expansion. This dichotomy represents the basis of a dilemma that has stumped immunologists for many years, how are self-specific T cells tolerized in the periphery? There appear to be two important criteria used to achieve this goal. The first is that in the absence of inflammatory pathogens, tolerance is promoted when T cells recognize antigen presented by quiescent dendritic cells (DCs) expressing low levels of costimulatory molecules. A second critical factor that defines "self" and drives tolerance through deletion, anergy, or suppression is the persistence of antigen.

Antigen Presentation↗
PubMed2000

Neonatal tolerant immunity for vaccination against autoimmunity.

Autoimmunity arises when the immune system no longer tolerates self and precipitates lymphocyte reactivity against our own antigens. Although the developing T cell repertoire is constantly purging, self-recognition events do exist when such tight control is evaded and autoreactive lymphocytes escape the thymus (the sites of T cell development) and migrate to the periphery. Upon activation these autoreactive cells may exert aggressive behavior toward one's own tissues and organs leading to autoimmune disease. Multiple sclerosis, Rheumatoid arthritis, and type I diabetes are autoimmune diseases mediated by autoreactive T cells. A logical approach to prevent such autoimmunity would be to reprogram those lymphocytes to tolerate the self antigen. Injection of antigen at the neonatal stage promotes a state of tolerance such that successive encounter with antigen does not precipitate aggressive reactions. The mechanism underlying neonatal tolerance involves priming of T cells whose effector functions do not cause inflammatory reactions upon recognition of antigen but rather induce protective immunity. This form of tolerant immunity provides an attractive strategy for vaccination against autoimmunity. Herein, it is shown that neonatal exposure to a self-peptide-immunoglobulin chimera drives a tolerant immunity toward the self-peptide and protects against the autoimmune disease, experimental allergic encephalomyelitis.

Animals↗
PubMed2004

Specialization in tolerance: innate CD(4+)CD(25+) versus acquired TR1 and TH3 regulatory T cells.

The regulation of immune responses to self-antigens is a complex process that involves maintaining self-tolerance while retaining the capacity to mount robust immune responses against invading microorganisms. Over the past few years, many new insights into this process have been gained, leading to the reemergence of the idea that regulatory T cells (Treg) are key players in immune regulation. These insights have raised fundamental questions concerning the definition of a Treg and what exactly constitutes T-cell-mediated suppression, identification of the signals and the cellular environment that promote the development and differentiation of these cells, and which signals maintain the homeostasis of the immune system. Thus far, the different models where Treg have been characterized cannot fully account for CD(4+)CD(25+) T cells. In this article, the authors propose the coexistence of two specialized types of CD(4+) Treg-innate and acquired-that differ in terms of their development, specificity, mechanisms, and sites of action.

Animals↗
PubMed2001

Intact B cell tolerance in the absence of the first component of the classical complement pathway.

A critical role for complement in the regulation of self tolerance has been proposed to explain the strong association between complement deficiency and autoimmunity. To elucidate the role of the classical pathway of complement in the maintenance of B cell tolerance, C1q-deficient (C1qa-/-) mice were bred with anti-hen egg lysozyme (HEL) immunoglobulin (Ig(HEL)) and soluble HEL (sHEL) transgenic mice. B cell tolerance was intact in C1qa-/- mice. In vivo, double-transgenic (Ig(HEL)/sHEL) C1qa-/- and wild-type control mice down-regulated surface immunoglobulin expression on splenocytes and equivalent numbers of HEL-binding B cells accumulated in the periphery. Maturation of B cells, evidenced by CD21 expression, was retarded to the same extent and at a similar time point. The frequency of anti-HEL-producing plasma cells and serum levels of anti-HEL immunoglobulin were comparably reduced in control and C1qa-/- double-transgenic mice compared to control Ig(HEL) and C1qa-/- Ig(HEL) mice. Furthermore, splenocytes from double-transgenic C1qa-/- or wild-type mice did not modulate intracellular calcium levels after stimulation with HEL in vitro. These data demonstrate that a stable form of B cell anergy persists in the periphery of C1qa-/- mice, suggesting that activation of the classical pathway by C1q is not essential for the maintenance of B cell tolerance in this transgenic model.

Animals↗
PubMed1991

A transgenic approach to the study of peripheral T-cell tolerance.

There is now convincing evidence for the imposition of self tolerance by means of the clonal deletion of self-reactive T cells operating within the thymus. Since not all self components may be encountered there, the question must be asked whether tolerance can occur post-thymically. To test this, we and other investigators have used transgenic technology to direct expression of a known "nonself" gene to a given extrathymic tissue. No lymphocytic infiltration was ever seen in transgene-expressing tissues, even if the mice were given normal syngeneic (nontransgenic) spleen cells intravenously or were stimulated with H-2Kb spleen cells. Infiltration did, however, occur in irradiated transgenic recipients of H-2Kb immune spleen cells. In MET-Kb mice, this infiltrate diminished with time, raising the possibility that peripheral tolerance may even have been induced in immune cells. H-2Kb-bearing skin was accepted in young RIP-Kb mice but rejected in older mice, which had lost more than 75% of their beta cells as a result of the overexpression of H-2Kb. This loss of tolerance thus occurred when the concentration of the tolerogen, H-2Kb, fell below some critical threshold. Following in vitro stimulation, spleen cells from young RIP-Kb mice could not kill H-2Kb-bearing targets, but could respond to third party targets. Thymus cells, on the other hand, could be stimulated to kill both targets, clearly indicating that tolerance was not imposed intrathymically. Spleen cells from older RIP-Kb mice (those that had lost most of their beta cells) killed both targets, which is in agreement with the in vivo data. Reactivity to H-2Kb was restored to young spleen cells by providing them with IL-2. Two hypotheses were proposed to account for the above findings: tolerance results either from the deletion or functional silencing of high-affinity effector cells or of regulatory, IL-2-producing helper T cells. As it is difficult to distinguish between these, we have produced a second series of transgenic mice (F3+) with rearranged TCR genes encoding an anti-H-2Kb TCR and derived "double-transgenic" (F3+RIP+) offspring by mating these mice with RIP-Kb mice. The transgenic TCR utilized the V beta 11 segment which can be detected by a monoclonal antibody. There were in the thymus very few CD4+ and very few CD4+8+ cells in both F3+ and F3+RIP+ mice and, in the double-transgenic mice, there was no evidence of deletion of CD8+V beta 11+ cells in the periphery although they showed tolerance to H-2Kb-bearing skin.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗