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At least 19 recordsLinked to original sources
PubMed1995

Self tolerance to T cell receptor V beta sequences.

T cell tolerance to self is achieved by deletion or inactivation of clones recognizing peptides of self proteins presented by major histocompatibility complex molecules. A considerable fraction of self proteins accessible to the immune system is contributed by the system itself, for example, the receptors used for antigen recognition (antibodies and T cell receptors [TCRs]). Thus far, it has remained unclear, whether antigen receptors are subject to self tolerance, or on contrary, engage into network interactions implying immunity rather than tolerance. In this study, we demonstrate self tolerance to synthetic peptides corresponding to the first hypervariable region of the V beta 8.1 and V beta 8.2 TCR proteins. We also show that the tolerogenic synthetic peptide corresponds to a fragment produced by processing of the V beta protein, and conversely, that a V beta peptide not produced by processing is also not subject to self tolerance. Thus, the rules of tolerance seem to apply to antigen receptors, at least to their germline-encoded portions, in a similar fashion as to other self proteins. This finding has important implications for studies of natural and artificially induced immune networks.

Amino Acid Sequence↗
PubMed1991

The fail-safe paradigm of immunological self-tolerance.

Immunological self-tolerance is guaranteed by several complementary mechanisms arranged in a fail-safe hierarchy--namely, clonal deletion, inactivation, and suppression. Only failure of all these self-tolerance-preserving systems allows autoimmune disease to develop. The notion of such a fail-safe organisation of the immune system is compatible with several features of autoimmune disease: its multicausal nature, its slowly progressive and relapsing course, and the diverse range of interventions available to restore autotolerance. This hypothesis has practical implications for the understanding of both the pathogenesis of iatrogenic autoimmune disease and the design of strategies to re-establish self-tolerance.

Autoimmune Diseases↗
PubMed1995

Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.

Approximately 10% of peripheral CD4+ cells and less than 1% of CD8+ cells in normal unimmunized adult mice express the IL-2 receptor alpha-chain (CD25) molecules. When CD4+ cell suspensions prepared from BALB/c nu/+ mice lymph nodes and spleens were depleted of CD25+ cells by specific mAb and C, and then inoculated into BALB/c athymic nude (nu/nu) mice, all recipients spontaneously developed histologically and serologically evident autoimmune diseases (such as thyroiditis, gastritis, insulitis, sialoadenitis, adrenalitis, oophoritis, glomerulonephritis, and polyarthritis); some mice also developed graft-vs-host-like wasting disease. Reconstitution of CD4+CD25+ cells within a limited period after transfer of CD4+CD25- cells prevented these autoimmune developments in a dose-dependent fashion, whereas the reconstitution several days later, or inoculation of an equivalent dose of CD8+ cells, was far less efficient for the prevention. When nu/nu mice were transplanted with allogeneic skins or immunized with xenogeneic proteins at the time of CD25- cell inoculation, they showed significantly heightened immune responses to the skins or proteins, and reconstitution of CD4+CD25+ cells normalized the responses. Taken together, these results indicate that CD4+CD25+ cells contribute to maintaining self-tolerance by down-regulating immune response to self and non-self Ags in an Ag-nonspecific manner, presumably at the T cell activation stage; elimination/reduction of CD4+CD25+ cells relieves this general suppression, thereby not only enhancing immune responses to non-self Ags, but also eliciting autoimmune responses to certain self-Ags. Abnormality of this T cell-mediated mechanism of peripheral tolerance can be a possible cause of various autoimmune diseases.

Animals↗
PubMed1987

Self tolerance and localized autoimmunity. Mouse models of autoimmune disease that suggest tissue-specific suppressor T cells are involved in self tolerance.

Autoimmune diseases appeared frequently in adults in the prostate and stomach of C3.129 mice after thymectomy on day 3 (Tx-3) without any additional treatment. Lesions of both organs could be completely prevented by a single i.p. injection of spleen cells from syngeneic adult mouse on day 4. For prevention of prostatis, the most effective cell source was normal males (4 X 10(6); normal females or Orx-0 males were less effective as the cell source, and higher doses of cells (4 X 10(7)) were needed. In contrast, spleen cells (4 X 10(6)) from these three donors had equivalent capacity for the prevention of gastritis. Similar autoimmune prostatis developed at very high frequency when spleen cells (4 X 10(6)) from normal females or Orx-0 males, but not from normal males, were injected i.p. into C3.129 nu/nu mice at 4 d. However, no sign of prostatis was found in nu/+ recipients. Injection of a larger dose (4 X 10(7)) from the same donors was not effective for induction of prostatis. Gastritis could not be induced in nu/nu mice by this procedure. Injection of spleen cells from Tx-3 males or females was effective for induction of both prostatis and gastritis in nu/nu recipients. It was also shown that a T cell population (Thy-1.2+, Ig-) had the capacity to prevent and to induce autoimmune diseases. These results together strongly suggest a role for active tissue-specific suppressor T cells in self tolerance, and elimination of such T cell populations causes autoimmunity.

Animals↗
PubMed1988

Development of self-tolerance in normal mice. Appearance of suppressor cells that maintain adult self-tolerance follows the neonatal autoantibody response.

T cell populations from BALB/c mice at different ages were analyzed to determine when in development Ts cells specific for the anti-mouse RBC (MRBC) autoantibody response become activated. Previous studies have shown that adult CD8+ T cells actively suppress this autoimmune response and adult spleen cells depleted of CD8+ cells can generate an anti-MRBC response in culture with MRBC. The present results demonstrate that T cells from mice less than 1 wk of age do not suppress the in vitro anti-MRBC response of adult spleen cell populations depleted of CD8+ Ts cells. By 2 wk of age Ts cells are detectable in this anti-self response and reach adult levels by 3 wk of age. Non-specific "natural suppressor" cells normally present in neonatal spleen cell populations are unable to suppress this autoantibody response, although they are active in suppressing anti-SRBC responses in the same cultures. Before the appearance of Ts cells active in the anti-MRBC response, neonatal spleen cell populations can generate anti-MRBC antibody-forming cells, both spontaneously in vivo and in vitro. The in vitro anti-MRBC response of neonatal spleen cells was shown to be Ag driven and Ag specific. The ability of unfractionated spleen cells to generate this response in vitro declines with age and is relatively low by 3 wk. This decline in responsiveness occurs simultaneously with the appearance of suppression specific for the anti-MRBC response, suggesting that the two events may be causally related.

Aging↗
PubMed1990

Transgenic models of T-cell self tolerance and autoimmunity.

Self-tolerance is generally induced by intrathymic clonal deletion of T cells with reactivity directed to antigens synthesized within the thymus (Kappler et al. 1987, Kisielow et al. 1988). It may also be induced in peripheral T cells when these encounter antigens unique to extra-thymic tissues. Two transgenic models have been particularly useful in the study of peripheral self tolerance: in one model, a known antigen is expressed in a particular extra-thymic site; in the other, the T-cell repertoire is predominantly reactive to this antigen. We, and others, have shown that expression of class I or II MHC molecules in defined extra-thymic sites leads to a state of T-cell tolerance. To account for this, we have proposed two hypotheses which have different implications for autoimmune disease. According to one, tolerance is imposed by deletion or functional silencing of specific high-affinity cytolytic T cells; alternatively, the target cell for tolerance induction may be a regulatory IL-2-producing T-cell, rather than the effector cell itself. To distinguish between these hypotheses it is essential to examine the fate of T cells which have the potential to react to the transgene product. Since the frequency of such T cells is low and there is no dominant clonotype for H-2Kb, which is the class I molecule we used, it was necessary to create double transgenic mice by mating class I transgenic mice with transgenic mice whose T-cell pool was compared of cells reactive to H-2Kb and could be detected by an antibody directed to the TCR. Initial studies showed that such T cells did persist despite the presence of antigen to which they may be reactive. If these double transgenic mice can be shown to be tolerant, they will offer a rich source of tolerant T cells for detailed investigation of their phenotype and fate, and they will be most useful in enabling us to probe the mechanisms responsible for the induction of peripheral self tolerance. Transgenic mouse technology has also been used successfully to unravel the genetic influences which may lead to or prevent autoimmunity. In particular, we have prevented autoimmune diabetes in the nonobese diabetic mouse by introducing a non-NOD MHC class II gene and further work is implicating the failure of intrathymic positive selection of a protective cell as one step in the pathogenesis of diabetes in NOD mice.

Animals↗
PubMed1987

Relevance of autocytotoxic and autoregulatory lymphocytes in the maintenance of self tolerance.

The state of self tolerance may well be an amalgam of many processes including (but not necessarily limited to) clonal deletion and specific suppressor cell networks. Cells with autoaggressive potential are clearly present in the blood of healthy individuals and have been implicated in diseases states. Given the critical importance of maintaining self tolerance, it is not at all surprising that several mechanisms appear to play a role in this process. Attempts to harness and manipulate these various mechanisms in order to prevent allograft rejection or to treat autoimmune diseases should prove to be exciting areas of investigation in the years ahead.

Animals↗
PubMed1994

Differential patterns of T cell clonal deletion in neonatal H-2 tolerance and I-E/Mls induced self-tolerance.

The pattern of clonal deletion of putative I-E-reactive (V beta 11) and Mls-reactive (V beta 3) T cells was evaluated and compared by cytofluorographic and immunohistochemical methods in a model of neonatal H-2 tolerance and in I-E- or Mls-bearing strains of mice which normally delete these cell populations (self-tolerance). The ontogeny of deletion of V beta 11+ cells was studied by evaluating thymic changes from birth until maturity in B10.S (H-2s/I-E-), B10.A (H-2k/d/I-E+) and B10.S mice intravenously infused at birth with (B10.SxB10.A)F1 lymphohaematopoietic cells. The reduction in V beta 11+ cells was most prevalent in the medullary region of the naive B10.A and neonatally injected B10.S animals and was corroborated by flow cytometry which demonstrated a marked reduction in single CD4 and CD8 positive B beta 11 T cells when compared to naive B10.S mice. However, immunohistochemistry illustrated that 'deletion' was never complete since V beta 11+ cells remained in the thymic cortex and splenic lymphoid follicles. By comparison, DBA/2 mice (Mlsc+ and previously documented to have decreased levels of V beta 3+ cells) showed a different pattern of deletion of V beta 3+ T cells than what was found for T cells bearing V beta 11 in animals deleting this population. DBA/2 thymi contained fewer thymic V beta 3- cells and there was more complete elimination of these cells, particularly in the periphery, by flow cytometry and immunohistology. The mice which do not delete V beta 3 cells (Mlsc-) showed that the majority of V beta 3- cells were located in the medulla with a few cells distributed in the cortical region. This pattern was notably different than the distribution of V beta 11 cells in thymi. Despite their location by histology, the majority of remaining V beta 3+ cells were dual CD4/CD8 positive (CD4+CD8+) by flow cytometric analysis. Our data illustrate that V beta 11 and V beta 3 T cells appear to be eliminated (i.e. 'deleted') at similar stages of maturation (single positive) during self-tolerance as well as in a neonatal H-2 tolerance model. However, the degree of elimination and the location of the cells remaining in these mice is dramatically different, depending on which T cell population is being evaluated and which deleting ligand is presented intrathymically. Thus, the accepted tenet of dual CD4+CD8+ cells localizing to the thymic cortex appears to have exceptions.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Self tolerance to human A and B histo-blood group antigens exists at the B cell level and cannot be broken by potent polyclonal B cell activation in vitro.

It is generally considered that tolerance to self antigens is less complete in B than in T lymphocytes. However, B cell tolerance through either functional inactivation (anergy) or clonal deletion has been demonstrated in transgenic mice. In the present study, we investigated whether B cells specific for self A/B histo-blood group antigens can be detected in normal humans. It is a key feature of the ABO system that all normal individuals make natural antibodies against those A or B carbohydrates which are not present in their organism. To detect B cells by the limiting dilution approach we used a specific enzyme-linked immunosorbent assay for the quantitation of anti-A/B antibodies, and a culture system in which polyclonal B cell activation occurs through cell contact with EL4 thymoma cells. As was reported for other B cell studies, we frequently detected "polyreactive" immunoglobulin (Ig)M (but not IgG) with apparent autoreactivity but of uncertain significance regarding physiologic conditions. However, A- or B-specific B cell responses occurred with selective patterns in agreement with classical blood group serology in 14 individuals with A, B, AB or 0 blood group phenotypes: 1/11,600 B cells made anti-allo A/B IgM and 1/26,500 B cells such as IgG, while only 1/104,000 B cells apparently made anti-self A/B IgM and 1/350,000 B cells such as IgG. This shows self tolerance at the B cell level. Since anergy of B cells can frequently be broken by polyclonal B cell activation in vitro, and EL4 cells are potent B cell stimulators, the present results argue for either a highly resistant anergic state or for clonal deletion of self-A/B histo-blood group-specific human B cells.

ABO Blood-Group System↗
PubMed1989

Interception of the development of self tolerance in fetal lambs.

Investigation of the nature of immunological self tolerance has usually relied upon experimental protocols in which the tolerant state is interrupted in mature animals with the production of autoimmune disease. While such research has improved the understanding of those processes operative in overt autoimmunity, it has not been informative in relation to events associated with the establishment of self tolerance. Any description of this state which is to be based on observation will necessitate the use of experimental systems that permit observation of animals during the development of self tolerance. The present experiment entailed intervention approximately one third of the way through the gestation period of fetal lambs. An earlier experiment had established that 54-day fetal lambs would accept allografts of adult skin. This indicated that the capacity to discriminate between self and non-self had not been acquired at that age. Fetuses at this stage of gestation were submitted to either partial or total removal of the thyroid gland. The excised tissue was then implanted in nude mice for periods of 5 to 9 weeks. It was subsequently replaced subcutaneously, either in the original donor or in another fetus at a comparable stage of gestation. At postmortem examination, several weeks later, self implants in lambs from which the thyroid gland had been completely removed displayed autoimmune thyroiditis of varying degrees of severity. However, self implants in partially thyroidectomized animals were uniformly free from autoimmune manifestations. This implied that these reactions had not been directed against contaminating murine tissues in the implants replaced in completely thyroidectomized lambs. All allogeneic implants were subject to vey heavy lymphocytic infiltration, usually with accompanying necrosis consistent with allograft rejection. This was taken as an indication that hypothyroid fetal lambs had become immunocompetent by the time of thyroid reimplantation. Spontaneous immunological reactivity against reimplanted self thyroid tissue by thyroidectomized lambs was interpreted as a failure to acquire the capacity for self recognition as a result of antigen deprivation.

Animals↗
PubMed1980

Is self tolerance H-2 restricted?

An individual's immune system must be capable of responding to a wide variety of antigens, but must not react against tissues of the individual itself. The specificity of this 'self tolerance' is determined early in life and recent work has dealt with the mechanisms by which self tolerance is maintained. We report here a study designed to determine whether products of the major histocompatibility complex are involved in the induction of self tolerance; in particular, whether the induction of self tolerance in the mouse is H-2 restricted. H-2 restriction refers to the finding that mouse T cells generally recognize foreign antigens only when presented in association with the products of H-2 alleles. We questioned whether T-cell precursors are made tolerant directly by antigen alone, or whether the antigen must be associated in the cell membrane with an appropriate H-2 molecule. We find that T-cell tolerance to 'self' membrane components does not seem to be H-2 restricted and discuss the possibility that this apparent lack of H-2 restriction is due to antigen processing.

Animals↗
PubMed1991

Maintenance of self tolerance in CD4+ T lymphocytes by antigen presentation on resting B cells--a hypothesis.

Self tolerance in the immune system is established by clonal deletion or induction of clonal anergy in immature lymphocytes. In addition, repair mechanisms for self tolerance working in the mature immune system may exist to take care of self-reactive lymphocytes eventually leaking through the central mechanisms. Two possible repair mechanisms for self tolerance, both capable of self/nonself discrimination, are discussed in this article. The first is the so-called veto function, which works on CD8+ T cells. The second is a new hypothesis suggesting that CD4+ T cells may be anergized by recognizing antigen on self-specific, anergic B cells.

Animals↗
PubMed1990

Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance.

During development in the thymus, T cells are rendered tolerant to self antigens. It is now apparent that thymocytes bearing self-reactive T cell receptors can be tolerized by processes that result in physical elimination (clonal deletion) or functional inactivation (clonal anergy). As these mechanisms have important clinical implications for transplantation and autoimmunity, current investigations are focused on understanding the cellular and molecular interactions that generate these forms of tolerance.

Animals↗
PubMed1989

A nondeletional mechanism of thymic self tolerance.

T cells become tolerant of self antigens during their development in the thymus. Clonal deletion of thymocytes bearing self-reactive T cell receptors is a major mechanism for generating tolerance and occurs readily for antigens expressed by bone marrow-derived cells. Tolerance to antigens expressed on the radioresistant thymic stromal elements is demonstrated here to occur via a nondeletional mechanism. For minor lymphocyte stimulatory (Mls-1a) and major histocompatibility complex (MHC) antigens, this alternate form of tolerance induction results in clonal anergy.

Animals↗
PubMed1979

Role of prethymic cells in acquisition of self-tolerance.

The sequential character of T-lymphocyte development as it pertains to the stage at which self-tolerance is acquired was investigated. Three phases were studied, defined here as prethymic, intrathymic, and postthymic as determined by the timing of thymus implantation. The model utilized was the temporal pattern of skin graft rejection in thymusless BALB/c nude mice implanted with allogeneic, C57BL/6J, or syngeneic thymuses before or after skin grafting; in some instances, F(1) hybrid spleen cells were also given to newborns or young adults. These experiments in nude mice showed that, (a) self-tolerance could be established despite the absence of the host's own haplotype in the implanted thymus; (b) recently emigrated postthymic cells could already discriminate self from non-self; (c) specific neonatal tolerance could be induced in nudes by inoculation of F(1) hybrid cells; (d) nudes showed a higher capacity for induction of neonatal tolerance than did normal littermates. These findings indicate that the process of self-tolerance in the T cell's lineage begins during the prethymic state early in ontogeny.

Animals↗
PubMed1992

Mechanisms of self tolerance.

The redundancy of biological systems minimizes the probability that isolated molecular and cellular defects entail deleterious consequences. This notion also applies to the establishment and maintenance of tolerance to self antigens. Thus, immune homeostasis is attributed to multiple distinct safety valves that are connected in series and intervene at defined control points of the life cycle of the developing lymphocyte to guarantee the physical elimination, functional inactivation, or regulated inhibition of self-reactive, potentially autoaggressive, B and T cells.

Animals↗
PubMed1988

Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex.

In mice the product of the Mlsa locus is an unusual antigen capable of interaction with certain products of the major histocompatibility locus (MHC) to form a ligand for a large portion of the T-cell alpha/beta receptor repertoire, including nearly all receptors that use V beta 8.1. The presence of Mlsa/MHC during T-cell development results in the deletion of T cells that express V beta 8.1, documenting the importance of clonal deletion in establishing tolerance to self antigens.

Animals↗