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PubMed1984

The delayed ontogenesis of Ia-positive macrophages: implications for host defense and self-tolerance in the neonate.

We have recently compared a number of macrophage functions in new-born and adult mice. In the adult, the most efficient resistance against Listeria infection requires a number of macrophage-T lymphocyte interactions which ultimately result in activated macrophages which eliminate the bacteria. A subpopulation of adult macrophages are distinguished by the presence of cell-surface; immune-response-gene-associated (Ia) antigens. These macrophages ingest and then "present" antigen to and thus activate T lymphocytes. Extensive in vitro experiments have shown that T lymphocyte activation requires both antigen and Ia-bearing macrophages. Ia-negative macrophages are not involved in this process. The T lymphocyte thus stimulated secretes lymphokines which then activate macrophages to acquire bactericidal and tumoricidal activity. In contrast to the adult mouse, essentially no Ia-bearing antigen presenting macrophages can be found in the neonatal spleen and peritoneal cavity. Neonatal and adult macrophages were similar in all other examined aspects--phagocytic activity, cytocidal function after lymphokine stimulation, and interleukin-1 secretion after exposure to endotoxin. The absence of Ia-bearing macrophages in neonates would be expected to contribute to their increased susceptibility to Listeria. The absence of Ia-bearing macrophages in the neonate is not the result of any intrinsic defects in these cells, as they can be made to express Ia in vitro. Nor is the deficit in Ia-bearing macrophages due to the hyporeactivity of neonatal helper T lymphocytes as adult athymic mice have significant numbers of Ia-bearing macrophages. Neonatal splenocytes or their conditioned media inhibit macrophage Ia expression when transferred into adult mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1995

[Characterization of tolerogen-producing cells and lymphoid tissues where self-tolerance is induced--a study on allogeneic bone marrow chimeras established with spontaneous leukemia prone mice].

SL/Kh strain of mice provides a spontaneous pre-B cell leukemia model and AKR/J mice provides a spontaneous thymoma model. Using these leukemia-prone mice, protective influence of bone marrow (BM) transplantation and tolerance induction to a host antigen, Mls-1a, after BM reconstitution were studied. When SL/Kh mice were reconstituted with BM cells from allogeneic C57BL/6 mice, these [B6-->SL] chimeric mice survived longer than non-treated SL or [SL-->SL] syngeneic chimeras. These findings are compatible to those obtained with [B6-->AKR] chimeras. In [D2-->SL] and [D2-->AKR] chimeras, V beta 6+ T cells reactive to Mls-1a had been clonally eliminated 5 weeks after BM reconstitution. On the other hand, minor graft versus host reaction (GVHR) abrogated the clonal elimination of V beta 6+ T cells in both [D2-->SL] and [D2-->AKR] chimeras. This abrogation appeared to be attributable to early disappearance of Mls-1a producing host T cells in the GVHR chimeras. The cells responsible for the Mls-1a production were revealed to be mainly CD8+CD44+ T cells by in vitro mixed lymphocyte reaction (MLR), although other T cell subsets also induced MLR under certain conditions. Administration of the CD8+CD44+ T cells from (AKR x BR)F1 mice induced clonal elimination of V beta 6+ T cells in the thymus and lymph nodes of [BR-->BR] syngeneic chimeras. By contrast, CD8+CD44- T cells induced partial reduction of V beta 6+ T cells only in lymph nodes. CD4+ T cells of Mls-1a type showed no tolerogenicity in this in vivo study, although these CD4+ T cells as well as CD8+ T cells evoked potentially MLR against Mls-1a. The present findings indicate that host CD8+CD44+ T cells are a major source of Mls-1a production in [Mls-1b-->Mls-1a] BM chimera system and suggest that CD44 expression on T cells is associated not only with high Mls-1a production but also with lymphoid tissues where the tolerogenic cells migrate.

Animals↗
PubMed1984

Mechanisms in immune tolerance.

Self:nonself-discrimination is critical for the function of the immune system and survival of vertebrate species. The failure to respond to one's own antigens has been called self-tolerance. The mechanisms whereby such tolerance may be induced are reviewed herein. Emphasis is placed on the role of self-recognition involving suppressor T-cell pathways as well as on studies involving putative clonal deletion mechanisms. The important parameters for the induction of tolerance and the roles played by surface isotypes in discriminating immunogenic vs. tolerogenic signals will be emphasized. The possible involvement of multiple pathways for self or experimental tolerance is emphasized with the ultimate goal being the modulation of aberrant immune responses.

Animals↗
PubMed1992

Post-thymic tolerance to self antigens.

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 have used transgenic technology to direct expression of a known 'non-self' gene, H-2Kb, to the insulin producing beta cells of the pancreas of mice. H-2Kb-bearing skin, but not skin from other mouse strains, failed to be rejected by the 'RIP-Kb' transgenic mice indicating specific tolerance. Following in vitro stimulation, their spleen cells could not kill H-2Kb-bearing targets, but could respond to third party targets. Their reactivity to H-2Kb was restored by providing them with IL-2. Two hypotheses could account for the above: tolerance results either from the deletion or functional silencing of high affinity effector cytotoxic cells or of regulatory, IL-2-producing helper T cells. Since it is difficult to distinguish between these, we have produced a second series of transgenic mice with rearranged T cell receptor (TCR) genes encoding an anti-H-2Kb TCR, and obtained 'double transgenic' offspring by mating these mice with RIP-Kb mice. The TCR utilized the V beta 11 segment which can be detected by a monoclonal antibody. Although the double transgenic mice were tolerant of H-2Kb, there was no evidence of deletion of anti-H-2Kb T cells. It seems, therefore, that a non-deletional mechanism operates to induce post-thymic tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Determination of tolerance to self E alpha peptides by clonal elimination of H-2E reactive T cells and antigen presentation by H-2A molecules.

A series of three synthetic peptides spanning H-2E alpha k chain residues (90-110), (110-130), and (130-150) were synthesized and purified. Mice representative of H-2E- (B6, B10, B10.M, B10.Q, B10.S) and H-2E+ (B10.D2, B10.K, B10.RIII) were immunized with individual peptides and lymph node cells challenged in vitro. Both B6 and B10 mice respond to in vitro challenge to peptides (90-110) (cpm 20,000), (110-130) (cpm 40,000), and (130-150) (cpm 60,000). In contrast all H-2E+ haplotypes were unresponsive to all three peptides (cpms < 10,000). Furthermore, B10 mice could be rendered hyporesponsive to E alpha k peptide challenge following expression of an E alpha k transgene or mating to an H-2E+ strain. The H-2Ad,k,f,q,s alleles were associated with reduced peptide recognition. Furthermore, alteration of the H-2A beta chain in bm12 mutant mice resulted in impaired responses to all three peptides. Immunization with synthetic peptides comprising major histocompatibility molecules may yield insights into mechanisms of self-tolerance.

Amino Acid Sequence↗
PubMed1996

The thymus and central tolerance.

Thymic selection programs T lymphocytes to tolerate self antigens but respond to foreign antigens. The mechanisms involved in self tolerance induction are discussed.

Animals↗
PubMed1990

Tolerance to self-antigens in transgenic mice.

Transgenic mice represent a versatile experimental approach for understanding the pathways by which the immune system regulates responsiveness to self-antigens, thereby establishing self-tolerance. The introduction of immunoglobulin and T cell receptor genes with specificity for self-antigens into the germline of mice has enabled the fate of self-reactive lymphocyte precursors to be followed in vivo. The influence of both developmentally regulated, and tissue-specific gene expression on tolerance to self-antigens has been addressed using transgenic mice expressing novel self-antigens under the transcriptional control of heterologous gene promoters. The generation of transgenic mice expressing structurally altered forms of self-antigens has allowed the role of antigen-processing in the induction of tolerance to be examined. Significantly, while these studies have confirmed the classically derived principles of immunological self-tolerance, they also point to the existence of pathways, as yet undefined, by which tolerance to self-antigens may be implemented and maintained.

Animals↗
PubMed1999

Expansion of neonatal tolerance to self in adult life: II. Tolerance preferentially spreads in an intramolecular manner.

Newborn rats exposed to a myelin basic protein determinant acquired long-lasting resistance to experimental autoimmune encephalomyelitis induced by another determinant only if both determinants are co-administered in adult life. We demonstrate here that during the course of disease both the anti-self response and the tolerant state spread in an intramolecular and not an intermolecular manner. Mechanisms involved in tolerance elicitation and expansion are then explored using an in vitro system in which indirect suppression could be measured.

Aging↗
PubMed2005

Central tolerance: learning self-control in the thymus.

In the past few years, there has been a flurry of discoveries and advancements in our understanding of how the thymus prepares T cells to exist at peace in normal healthy tissue: that is, to be self-tolerant. In the thymus, one of the main mechanisms of T-cell central tolerance is clonal deletion, although the selection of regulatory T cells is also important and is gaining enormous interest. In this Review, we discuss the emerging consensus about which models of clonal deletion are most physiological, and we review recent data that define the molecular mechanisms of central tolerance.

Animals↗
PubMed1997

Role of Thy-1 in T cell development.

Tolerance to self proteins is accomplished in part by elimination of autoreactive immature T cells as they develop in the thymus. Although many investigators have studied the cellular interactions that regulate this important process, the specific molecules involved in negative selection are still not well understood. Thy-1 is a glycosyl-phosphatidylinositol-linked protein that is expressed at high levels on immature thymocytes, and recent evidence suggests that it is involved in thymocyte apoptosis. Correspondingly, we have found that Abs to Thy-1 block Ag-dependent thymocyte deletion in an in vitro culture system. Thus, we investigated the role of Thy-1 in T cell development by using Thy-1 -deficient mice containing a TCR transgene specific for a class II MHC-restricted Ag. With this system, the role of Thy-1 in Ag-specific self-restriction and self-tolerance could be analyzed. Thy-1-null mice were found to undergo normal negative selection in three different models: the in vitro culture system, anti-CD3-induced thymocyte deletion in vivo, and Ag-induced thymocyte deletion in vivo. Self-restriction to MHC class II also appeared to occur normally in Thy-1-null mice. These results therefore suggest that Thy-1 is not essential for either self-restriction or self-tolerance to MHC class II-restricted Ags. This finding is discussed in light of recent data regarding the role of other glycosyl-phosphatidylinositol-linked proteins in thymocyte development.

Age Factors↗
PubMed1993

The regulation of autoimmunity through CD4+ T cells.

Our experiments imply that it is possible to use monoclonal antibody therapy to reestablish self tolerance to self antigens. This can be achieved by using a short course of an nd anti-CD4 antibody thus avoiding the problem of long term immunosuppression. The mechanism by which such a state of self tolerance is achieved remains to be clarified but possible mechanisms include deletion or anergy of autoreactive T cells or some form of suppression mediated through local cytokine production. As this antibody induced state of tolerance can be reversed in the NOD mouse by cyclophospamide deletion cannot be the method by which autoreactivity is prevented. The mixing experiments which have been described in the thyroiditis experiments strongly suggest that anery is not the mechanism. It therefore remains most likely that tolerance induced following administration of nd anti-CD4 is an active process maintained through the production of an inhibitory cytokine. This ability to reprogram the immune system using monoclonal antibodies makes it not beyond the realms of possibility that individuals suffering from IDDM may become tolerant of their beta cell antigens and thus be able to regenerate their own beta cell mass. If this could indeed occur it might mean that a lifetime of insulin injections and the development of the life threatening complications that may accompany a disease like IDDM may be avoided.

Animals↗
PubMedDate not supplied

Simple developmental programs of gene expression and cellular composition of lymphoid organs at the origin of natural tolerance.

Self-tolerance is acquired in the embryonic/perinatal period, but new lymphocytes (that will have to distinguish between self and nonself) continue to be produced throughout life, after both self and nonself are present. This makes it impossible for natural tolerance to rely on recessive mechanisms. Recent observations on "dominant tolerance" have led to the hypothesis that natural tolerance is established as a consequence of simple developmental programs for gene expression and cellular composition of primary lymphoid organs. In development, the cellular composition of the thymus is predominantly epithelial, allowing for the positive selection and activation of "high avidity" self-reactive T cells that are not deleted because antigen presentation by haemopoietic cells is limiting. Such T cells, activated in that environment, display effector functions of a regulatory type that are maintained in the periphery upon restimulation by tissue peptides shared with the thymic epithelium. Recent thymic emigrants with specificity for tissue-specific antigens that are absent from the thymus will first encounter their ligands in the context of the "regulatory cell" recognition of ubiquitous peptides and are thus recruited into similar regulatory activities. In contrast, thymic emigrants with specificity for nonself antigens (absent during the perinatal period) are not activated intrathymically, reach the periphery as resting cells, and move out of the time window of susceptibility to functional recruitment. These will react "de novo" upon encounter of the respective antigens and will acquire the class of effector functions determined by the peripheral microenvironment in which they are activated. This strategy, which explains the thymic dependence of peripheral tissue-specific tolerance, may be re-enforced by developmental restrictions in cytokine gene expression, and it will ensure the establishment and maintenance of T-cell tolerance through the dynamic storage of a distributed memory of the embryonic self. B lymphocytes that are produced in the embryonic/perinatal period characteristically rearrange and express a few V-genes very predominantly. These V-genes encode antibodies with unique properties of "connectivity" to other V-regions, making it possible to establish a network that limits clonal expansions and/or terminal differentiation to antibody production. Self-reactive B cells are thus recruited into such a network which, by contributing to the molecular environment of the body and to the selection of emergent repertoires, leads to deletion of connected cells and to the "normalization" of the adult antibody repertoires. Natural autoantibody repertoires in the adult are thus recursively maintained, stable and continuously adjusted to the thresholds of single cell deletion and to the alterations in the body composition. The activity of self-specific regulatory T cells contributes to limiting clonal expansion and inhibiting somatic mutation of self-reactive B cells. This model explains a number of observations that were not included in the "clonal" and "recessive" tolerance views, and offers suggestions on mechanisms in physiological autoimmunity and pathology.

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