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PubMed1982

Can experimental B cell tolerance serve as a model for self tolerance?

We have examined the abilities of the mature and immature immune systems to discriminate between tolerogenic and nontolerogenic forms of a hapten-carrier conjugate; both forms are multivalent nonimmunogenic polymers of the same molecular weight, and have the same avidity for free, hapten-specific antibody and hapten-binding B cells. Hapten-specific tolerance was induced in adult B cells by nonimmunogenic dinitrophenylated carboxymethyl cellulose or methyl cellulose. Oxidation and subsequent reduction of the vicinal hydroxyl groups of both carriers aborgated tolerogenicity, although they remained nonimmunogenic. This chemical modification did not affect the carrier's molecular weight, and it did not reduce the binding avidity of their hapten derivatives to hapten-specific antibody or to antigen-binding B cells. The same experiments, when carried out in either neonatal mice or mice that had been lethally irradiated and given the above compounds during treatment with 13-day-old fetal liver cells, invariably yielded the same results. Like adult mice, these immunologically immature animals were capable of distinguishing between the tolerogenic and the nontolerogenic form of each antigen. It has also been shown (C. A. Waters et al., in preparation) that neonatally induced tolerance to TNP-HGG is irreversible, whereas tolerance to TNP-BSA is reversible by challenge with TNP-LPS. These results are in conflict with the clonal abortion hypothesis.

Aging↗
PubMed2006

Immunity to melanoma antigens: from self-tolerance to immunotherapy.

The development of effective immune therapy for cancer is a central goal of immunologists in the 21st century. Our laboratories have been deeply involved in characterization of the immune response to melanoma and translation of laboratory discoveries into clinical trials. We have identified a cohort of peptide antigens presented by Major Histocompatibility Complex (MHC) molecules on melanoma cells and widely recognized by T cells from melanoma patients. These have been incorporated into peptide-based vaccines that induce CD8(+) and CD4(+) T-cell responses in 80-100% of patients. Major objective clinical tumor regressions have been observed in some patients, and overall survival in vaccinated patients exceeds expected stage-specific survival. New clinical trials will determine the value of combination of melanoma helper peptides (MHP) into multipeptide vaccines targeting CD8 cells. New trials will also evaluate new approaches to modulating the host-tumor relationship and will develop new combination therapies. Parallel investigations in murine models are elucidating the immunobiology of the melanoma-host relationship and addressing issues that are not feasible to approach in human trials. Based on the fact that the largest cohort of melanoma antigens are derived from normal proteins concerned with pigment production, we have evaluated the mechanisms of self-tolerance to tyrosinase (Tyr) and have determined how T cells in an environment of self-tolerance are impacted by immunization. Using peptide-pulsed dendritic cells as immunogens, we have also used the mouse model to establish strategies for quantitative and qualitative enhancement of antitumor immunity. This information creates opportunities for a new generation of therapeutic interventions using cancer vaccines.

Animals↗
PubMed2003

A paragon of self-tolerance: CD25+CD4+ regulatory T cells and the control of immune responses.

The interest in naturally arising regulatory T (TR) cells as a paradigm for maintaining immunological self-tolerance has undergone an explosive re-emergence in recent years. This renaissance was triggered by several key experimental observations and the identification of specific molecular markers that have enabled the isolation and experimental manipulation of these cells. Although their existence was once controversial, a large body of evidence now highlights the critical roles of TR cells in maintaining immunological self-tolerance. Furthermore, abnormality of natural TR cells can be a primary cause of autoimmune and other inflammatory diseases in humans.

Journal Article↗
PubMed1997

The basis for self-tolerance of natural killer cells in beta2-microglobulin- and TAP-1- mice.

Cells from mice with mutations in the genes for beta2-microglobulin (beta2m) or for TAP-1 express only low levels of MHC class I proteins on their surfaces, and are thus sensitive to attack by normal NK cells. Although NK cells are present in beta2m- mice and TAP-1(-) mice, they are completely self-tolerant. The underlying mechanism for this tolerance is unknown. It has been proposed that education processes render NK cells from these mice hypersensitive to class I-mediated inhibition, so that they can be inhibited even by the low levels of class I expressed on autologous cells. In this study, we present evidence against this hypothesis, by demonstrating that NK cells from beta2m- mice and TAP-1(-) mice fail to attack beta2m(-)TAP-1(-) double-mutant cells in both in vitro and in vivo assays. The latter cells express substantially lower levels of class I than single-mutant cells, based on serologic tests, as well as a significantly diminished sensitivity to attack by class I-specific CTL. Furthermore, the Ly-49 repertoire on NK cells derived from beta2m(-)TAP-1(-) mice is highly similar to that of either single mutant, indicating that the developmental processes that shape the Ly-49 repertoire cannot respond to the differences in class I levels among these mice. We propose that self-tolerance of NK cells in beta2m- mice and TAP-1(-) mice is likely to result from hyporesponsiveness of the cells to activating signals, or alternatively, to induction of inhibitory signaling through receptors specific for non-class I MHC ligands.

Animals↗
PubMed1998

A critical role for complement in maintenance of self-tolerance.

The role of complement in the maintenance of self-tolerance has been examined in two models: an immunoglobulin transgenic model of peripheral tolerance and a lupus-like murine model of CD95 (Fas) deficiency. We find that self-reactive B lymphocytes deficient in complement receptors CD21/CD35 or transferred into mice deficient in the complement protein C4 are not anergized by soluble self-antigen. In the second model, deficiency in CD21/CD35 or C4 combined with CD95 deficiency results in high titers of anti-nuclear antibodies leading to severe lupus-like disease. These findings suggest a novel role for the complement system in B cell tolerance and provide insight into the genetic association of complement deficiency with susceptibility to systemic lupus erythematosus.

Animals↗
PubMed2002

The CD8alpha(+) dendritic cell is responsible for inducing peripheral self-tolerance to tissue-associated antigens.

We previously described a mechanism for the maintenance of peripheral self-tolerance. This involves the cross-presentation of tissue-associated antigens by a bone marrow-derived cell type that stimulates the proliferation and ultimate deletion of self-reactive CD8 T cells. This process has been referred to as cross-tolerance. Here, we characterize the elusive cell type responsible for inducing cross-tolerance as a CD8alpha(+) dendritic cell (DC). To achieve this aim, transgenic mice were generated expressing yellow fluorescent protein (YFP) linked to CTL epitopes for ovalbumin and glycoprotein B (gB) of herpes simplex virus under the rat insulin promoter (RIP). Although tracking of YFP was inconclusive, the use of a highly sensitive gB-specific hybridoma that produced beta-galactosidase on encounter with antigen, enabled detection of antigen presentation by cells isolated from the pancreatic lymph node. This showed that a CD11c(+)CD8alpha(+) cell was responsible for cross-tolerance, the same DC subset as previously implicated in cross-priming. These data indicate that CD8alpha(+) DCs play a critical role in both tolerance and immunity to cell-associated antigens, providing a potential mechanism by which cytotoxic T lymphocyte can be immunized to viral antigens while maintaining tolerance to self.

Animals↗
PubMed2000

Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4.

This report shows that cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) plays a key role in T cell-mediated dominant immunologic self-tolerance. In vivo blockade of CTLA-4 for a limited period in normal mice leads to spontaneous development of chronic organ-specific autoimmune diseases, which are immunopathologically similar to human counterparts. In normal naive mice, CTLA-4 is constitutively expressed on CD25(+)CD4(+) T cells, which constitute 5-10% of peripheral CD4(+) T cells. When the CD25(+)CD4(+) T cells are stimulated via the T cell receptor in vitro, they potently suppress antigen-specific and polyclonal activation and proliferation of other T cells, including CTLA-4-deficient T cells, and blockade of CTLA-4 abrogates the suppression. CD28-deficient CD25(+)CD4(+) T cells can also suppress normal T cells, indicating that CD28 is dispensable for activation of the regulatory T cells. Thus, the CD25(+)CD4(+) regulatory T cell population engaged in dominant self-tolerance may require CTLA-4 but not CD28 as a costimulatory molecule for its functional activation. Furthermore, interference with this role of CTLA-4 suffices to elicit autoimmune disease in otherwise normal animals, presumably through affecting CD25(+)CD4(+) T cell-mediated control of self-reactive T cells. This unique function of CTLA-4 could be exploited to potentiate T cell-mediated immunoregulation, and thereby to induce immunologic tolerance or to control autoimmunity.

Abatacept↗
PubMed1997

CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice.

Low doses of the CD3 mAb 145 2C11 restored self tolerance to beta cell Ags in adult overtly diabetic NOD mice. Within 2 to 4 wk after treatment, complete and permanent remission of diabetes was observed. Autoreactive T cells were not deleted in CD3 Ab-protected animals as evidenced first, by the persistence of peripheral insulitis and, second, by the capacity of spleen cells from CD3 Ab-treated mice to transfer diabetes to adult irradiated syngeneic recipients. Moreover, the conferred tolerance was reproducibly reversed by a single injection of cyclophosphamide. For 5 to 7 wk after treatment, IFN-gamma production by stimulated spleen cells was significantly decreased in treated animals. One unique feature was that the CD3 Ab-induced tolerance ensued only from treatment of overtly diabetic NOD mice. Durable protection was exclusively observed when treating mice with recent onset disease (14-20 wk old). At variance with this finding, treatment of 4- and 8-wk-old mice was without effect, and complete but transient protection followed the treatment of 12-wk-old NOD mice. The tolerogenic properties of 145 2C11 did not depend on its mitogenic capacity, since nonmitogenic F(ab')2 fragments also appeared potent at inducing durable remission in overtly diabetic NOD, although nonmitogenic CD3 F(ab')2 fragments could mediate T cell signaling, as evidenced by cytokine gene transcription (IL-2, IFN-gamma, IL-4, and IL-10) assessed by PCR on splenocytes from treated mice. A concomitant cyclosporine treatment abrogated the CD3 mAb-induced protection, further pointing to the crucial role of T cell signaling in the effect observed.

Adoptive Transfer↗
PubMed2005

Cellular and genetic mechanisms of self tolerance and autoimmunity.

The mammalian immune system has an extraordinary potential for making receptors that sense and neutralize any chemical entity entering the body. Inevitably, some of these receptors recognize components of our own body, and so cellular mechanisms have evolved to control the activity of these 'forbidden' receptors and achieve immunological self tolerance. Many of the genes and proteins involved are conserved between humans and other mammals. This provides the bridge between clinical studies and mechanisms defined in experimental animals to understand how sets of gene products coordinate self-tolerance mechanisms and how defects in these controls lead to autoimmune disease.

Animals↗
PubMed1985

Induction of self-tolerance and enhanced stress protein synthesis in L-132 cells by cadmium chloride and by hyperthermia.

The effect of heat shock or cadmium treatment on protein synthesis and cell survival in L-132 cells has been examined. After cadmium treatment, the synthesis of a polypeptide of Mr 68000 (P68) was greatly enhanced over that of untreated cells. Besides P68 the synthesis of another polypeptide of Mr 89000 (P89) was also enhanced in heat-shocked cells. Both heat shock and cadmium treatment induced self-tolerance. The kinetics of the synthesis of induced polypeptides correlated well with the development of self-tolerance. The patterns of peptide maps obtained after partial proteolytic digestion from P68 induced in cadmium-treated and heat-shocked cells were virtually identical. However, neither heat-shocked cells did not confer cadmium tolerance nor did cadmium-treated cells induce thermotolerance.

Actins↗
PubMed2003

Thymic generation and selection of CD25+CD4+ regulatory T cells: implications of their broad repertoire and high self-reactivity for the maintenance of immunological self-tolerance.

Besides positive and negative selection of T cells, another function of the thymus in maintaining immunological self-tolerance is the production of CD25+CD4+ regulatory T cells capable of preventing autoimmune disease. They acquire the regulatory activity through the thymic selection process, and are released to the periphery as a functionally and phenotypically mature population. Our recent study with transgenic mice in which every class II MHC molecule covalently binds the same single peptide has revealed that a particular self-peptide/MHC ligand in the thymus can positively select a broad repertoire of functionally mature CD25+CD4+ regulatory T cells as well as naive T cells. Interestingly, the regulatory T cells bear higher reactivity than other T cells to the selecting ligand in the thymus even after negative selection by the ligand. This broad repertoire and high self-reactivity of CD25+CD4+ regulatory T cells, together with their high level expression of various accessory molecules, may guarantee their prompt and efficient activation upon encounter with a diverse range of self peptide/MHC complexes in the periphery, ensuring dominant control of self-reactive T cells.

Animals↗
PubMed1999

Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance.

This study shows that the normal thymus produces immunoregulatory CD25+4+8- thymocytes capable of controlling self-reactive T cells. Transfer of thymocyte suspensions depleted of CD25+4+8- thymocytes, which constitute approximately 5% of steroid-resistant mature CD4+8- thymocytes in normal naive mice, produces various autoimmune diseases in syngeneic athymic nude mice. These CD25+4+8- thymocytes are nonproliferative (anergic) to TCR stimulation in vitro, but potently suppress the proliferation of other CD4+8- or CD4-8+ thymocytes; breakage of their anergic state in vitro by high doses of IL-2 or anti-CD28 Ab simultaneously abrogates their suppressive activity; and transfer of such suppression-abrogated thymocyte suspensions produces autoimmune disease in nude mice. These immunoregulatory CD25+4+8- thymocytes/T cells are functionally distinct from activated CD25+4+ T cells derived from CD25-4+ thymocytes/T cells in that the latter scarcely exhibits suppressive activity in vitro, although both CD25+4+ populations express a similar profile of cell surface markers. Furthermore, the CD25+4+8- thymocytes appear to acquire their anergic and suppressive property through the thymic selection process, since TCR transgenic mice develop similar anergic/suppressive CD25+4+8- thymocytes and CD25+4+ T cells that predominantly express TCRs utilizing endogenous alpha-chains, but RAG-2-deficient TCR transgenic mice do not. These results taken together indicate that anergic/suppressive CD25+4+8- thymocytes and peripheral T cells in normal naive mice may constitute a common T cell lineage functionally and developmentally distinct from other T cells, and that production of this unique immunoregulatory T cell population can be another key function of the thymus in maintaining immunologic self-tolerance.

Animals↗
PubMed1984

Mechanism of neonatally induced idiotype suppression and its relevance for the acquisition of self-tolerance.

We present an analysis of the elimination of a monoclonal anti-idiotope antibody injected into C57BL/6 mice on the day of birth. During the first 4 weeks of life the antibody is eliminated from the circulation with a slow half-life, ranging from 15-18 days. This finding makes sense biologically as the animals depend at that time on maternally transmitted antibodies. After 4 weeks elimination speeds up considerably. The rate of elimination appears to be the same for a 1 microgram and a 100 microgram dose. The elimination data and previous results on the specificity, duration and cellular basis of idiotype suppression induced by the monoclonal anti-idiotope fit into the following model of idiotype suppression, which is in good accord with other experimental evidence on idiotype and allotype suppression in the literature: suppression depends strictly on the concentration of anti-idiotope in the cellular environment. As long as it is in the microgram range, the generation of idiotope-bearing B cells from pre-B cells is prevented. The system recovers quickly from this type of suppression, as soon as the concentration of anti-idiotope falls below that range. A second type of suppression is also induced in the anti-idiotope-treated animals. It is long-lived (8-10 weeks longer that the first type), has a peculiar specificity in that it affects, in our particular case, only a certain subset of the antibodies bearing the target idiotope, and involves regulatory T (and possibly B) cells which prevent the functional maturation of B cells expressing those antibodies in the animal. Suppression of this type also depends strictly on anti-idiotope concentration and is induced either at the time when the generation of idiotope-bearing B cells from pre-B cells is still inhibited or just thereafter, when such cells begin to appear in the system and the anti-idiotope concentration is still at a few hundred nanograms per ml. Experimental evidence indicates that in the induction of suppression, the primary target of the anti-idiotope are idiotope-bearing antibodies variable regions. We assume that those variable regions, complexed by anti-idiotope are the inducers of regulatory (suppressive) T cells. Idiotype suppression may also be induced upon interaction of antibody variable regions (and possibly other receptors) with ligands other than anti-idiotypic antibodies. We, therefore, think that idiotype suppression not only establishes self-tolerance within the antibody system, but is a mechanism of self-tolerance in general.

Animals↗
PubMed1990

Suppression in experimental autoimmune thyroiditis: the role of unique and shared determinants on mouse thyroglobulin in self-tolerance.

Previous studies have shown that T cells from mice genetically susceptible to experimental autoimmune thyroiditis (EAT) recognize determinants shared between mouse thyroglobulin (Tg) and heterologous Tgs. Some shared determinants are thyroiditogenic; lymphocytes from mice immunized with mouse Tg (MTg) or human Tg (HTg) and reciprocally restimulated in vitro with either Tg can transfer EAT. Studies on the mechanisms of self-tolerance have shown that pretreatment with soluble MTg suppresses in vitro proliferation to MTg and EAT induction with MTg. To determine the role of share epitopes in maintaining tolerance, mice were pretreated with soluble HTg and immunized with HTg or MTg and adjuvant. Cells from HTg-pretreated. HTg-immunized mice showed suppressed in vitro proliferative response to HTg. Following MTg immunization, the cells showed suppressed in vitro response to MTg. However, in contrast to MTg pretreatment, the subsequent development of EAT in vivo was unaltered in severity following HTg pretreatment. Thus, determinants shared between HTg and MTg can induce suppression of in vitro responses to HTg and MTg, but not inhibit the onset of thyroiditis, suggesting that T cells recognizing MTg-unique epitopes expanded to mediate thyroiditis. We conclude that recognition of both unique epitopes expanded to mediate thyroiditis. We conclude that recognition of both unique and shared epitopes on MTg are essential for the overall maintenance of self-tolerance.

Animals↗
PubMed2004

The impact of self-tolerance on the polyclonal CD8+ T cell repertoire.

TCRs possess considerable cross-reactivity toward structurally related Ags. Because the signaling threshold for negative selection is lower than that required for activation of mature T cells, the question arises as to which extent thymic deletion of self-specific T cells affects T cell responsiveness toward foreign peptides. In this study we show, in three different mouse models systems, that the polyclonal CD8(+) T cell repertoire has a marked ability to react against the majority of Ags related to self despite self-tolerance, even in cases where self and foreign differ only marginally at a single TCR-contact residue. Thus, while individual T cells are markedly cross-reactive, the ability to distinguish between closely related Ags is introduced at the polyclonal T cell level.

Amino Acid Substitution↗
PubMed2000

Transgenic expression of an immunologically privileged retinal antigen extraocularly enhances self tolerance and abrogates susceptibility to autoimmune uveitis.

Interphotoreceptor retinoid-binding protein (IRBP) is an immunologically privileged retinal antigen that can elicit experimental autoimmune uveitis (EAU). The nature and extent of tolerance to immunologically privileged self antigens is poorly understood. To investigate whether transgenic expression of IRBP extraocularly enhances tolerance and protects from EAU we prepared mice that express half of the mouse IRBP gene, containing a potent uveitogenic epitope (residues 161 - 180), under control of MHC class II promoter. Transgene mRNA was detectable in many tissues. Transgenic protein was undetectable by conventional assays, but was detected in thymic tissue by lymphocyte proliferation assay after induction of the promoter. Transgenic mice challenged with p161 - 180 did not develop EAU and had reduced immunological responses, but remained susceptible to EAU induced by whole IRBP, that contains additional uveitogenic epitopes. Disease was also induced by wild type T cells specific to p161 - 180. Thus, extraocular expression of a privileged retinal antigen enhances self tolerance, supporting the notion that sequestration contributes to immune privilege. Exceedingly low levels of transgene expression result in tolerance that is both profound and epitope specific, implying anergy or deletion of the endogenous uveitogenic repertoire. The same level of expression is, however, insufficient to tolerize wild-type effector T cells in the periphery.

Amino Acid Sequence↗
PubMed2003

Naturally arising CD25+CD4+ regulatory T cells in maintaining immunologic self-tolerance and preventing autoimmune disease.

A large body of evidence indicates that T cell-mediated dominant suppression of self-reactive T cells is indispensable for maintaining immunologic unresponsiveness to self-constituents (i.e., self-tolerance) and preventing autoimmune disease. CD25+CD4+ regulatory T cells naturally present in normal animals, in particular, engage in this function, as their reduction or functional abnormality leads to the development of autoimmune disease in otherwise normal animals. They are at least in part produced by the normal thymus as a functionally mature and distinct subpopulation of T cells. Recent studies have demonstrated that CD25+CD4+ regulatory T cells control not only autoimmune reactions but also other immune responses, including tumor immunity, transplantation tolerance and microbial infection. Thus, this unique population of regulatory T cells can be exploited to control pathological as well as physiological immune responses.

Animals↗
PubMed2004

Regulating self-tolerance by deregulating gene expression.

Intrathymic expression of peripheral auto-antigens, termed promiscuous gene expression, extends the scope of central T-cell tolerance to peripheral organs and proves essential for the induction and maintenance of self-tolerance. The purification of antigen-presenting cells has been instrumental in identifying promiscuous gene expression as an inherent property of medullary epithelial cells. The pool of promiscuously expressed genes might encompass up to 10% of the whole genome. The remarkable diversity of this gene pool implies a complex mode of regulation, which cannot be solely explained by the action of a single factor, such as the transcriptional autoimmune regulator AIRE. Co-localization of promiscuously expressed genes in clusters also suggests epigenetic mechanisms (e.g. DNA methylation) to account for this unorthodox gene expression pattern. The identification of the molecular components controlling the expression of tissue-restricted genes in the thymus promises to add valuable new insights into the complex genetic regulation underlying most autoimmune diseases.

Animals↗