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PubMed1995

Central tolerance of T cells.

The immune system is constructed to tolerate self antigens but give vigorous responses to foreign antigens. How this state of self/nonself discrimination is maintained is controversial. In the case of T cells, many self antigens are transported to the thymus via the bloodstream and induce tolerance (clonal deletion) of self-reactive thymocytes in situ. Although such central tolerance in the thymus is well documented, it is often argued that full induction of tolerance requires peripheral mechanisms such as suppression or induction of anergy. This article proposes that steady-state tolerance of T cells to self components is due solely to central tolerance to circulating self antigens combined with sequestration of tissue-specific antigens. Backup mechanisms for tolerance do exist but such immunoregulation only operates when self tolerance breaks. This scheme allows the immune system to give unrestricted primary responses to foreign antigens.

Animals↗
PubMed2005

Regulation of murine chronic colitis by CD4+CD25- programmed death-1+ T cells.

Naturally arising CD4(+)CD25(+) regulatory T (T(R)) cells are engaged in the maintenance of self tolerance and prevention of autoimmune diseases. However, accumulating evidence suggests that a fraction of peripheral CD4(+)CD25(-) T cells also possesses regulatory activity. Programmed death-1 (PD-1) is a new member of the CD28/CTLA-4 family, which has been implicated in the maintenance of peripheral self tolerance. Here, we identified a subpopulation of CD4(+)CD25(-)PD-1(+) T cells in the spleen of naive mice that constitutively expressed CTLA-4 and FoxP3 and was hypoproliferative in response to anti-CD3 antibody stimulation in vitro. However, the CD4(+)CD25(-)PD-1(+) T cells uniquely produced large amounts of IL-4 and IL-10 in response to anti-CD3 and anti-CD28 mAb stimulation, unlike the CD4(+)CD25(+) T(R) cells. The CD4(+)CD25(-)PD-1(+) T cells exhibited a suppressor activity against the proliferation of anti-CD3 antibody-stimulated CD4(+)CD25(-)PD-1(-) T cells in vitro, which was partially abrogated by anti-CTLA-4 mAb, but not by anti-IL-10 or anti-PD-1 mAb. Remarkably, the CD4(+)CD25(-)PD-1(+) T cells inhibited the development of colitis induced by adoptive transfer of CD4(+)CD45RB(high) T cells into C.B17-scid/scid mice, albeit to a lesser extent than CD4(+)CD25(+) T(R) cells, in a CTLA-4-dependent manner. These results indicate that the CD4(+)CD25(-)PD-1(+) T cells contain substantial amounts of T(R) cells that are involved in the maintenance of peripheral tolerance.

Animals↗
PubMed2005

Dendritic cells in human thymus and periphery display a proinsulin epitope in a transcription-dependent, capture-independent fashion.

The natural expression of tissue-specific genes in the thymus, e.g., insulin, is critical for self-tolerance. The transcription of tissue-specific genes is ascribed to peripheral Ag-expressing (PAE) cells, which discordant studies identified as thymic epithelial cells (TEC) or CD11c+ dendritic cells (DC). We hypothesized that, consistent with APC function, PAE-DC should constitutively display multiple self-epitopes on their surface. If recognized by Abs, such epitopes could help identify PAE cells to further define their distribution, nature, and function. We report that selected Abs reacted with self-epitopes, including a proinsulin epitope, on the surface of CD11c+ cells. We find that Proins+ CD11c+ PAE cells exist in human thymus, spleen, and also circulate in blood. Human thymic Proins+ cells appear as mature DC but express CD8alpha, CD20, CD123, and CD14; peripheral Proins+ cells appear as immature DC. However, DC derived in vitro from human peripheral blood monocytes include Proins+ cells that uniquely differentiate and mature into thymic-like PAE-DC. Critically, we demonstrate that human Proins+ CD11c+ cells transcribe the insulin gene in thymus, spleen, and blood. Likewise, we show that mouse thymic and peripheral CD11c+ cells transcribe the insulin gene and display the proinsulin epitope; moreover, by using knockout mice, we show that the display of this epitope depends upon insulin gene transcription and is independent of Ag capturing. Thus, we propose that PAE cells include functionally distinct DC displaying self-epitopes through a novel, transcription-dependent mechanism. These cells might play a role in promoting self-tolerance, not only in the thymus but also in the periphery.

Animals↗
PubMed1990

Autoantigen processing and the mechanisms of tolerance to self.

Large foreign protein antigens are processed in antigen presenting cells before they can be recognized by T lymphocytes. The processing involves the ingestion of the antigen, a controlled proteolytic fragmentation, and the association of immunogenic fragments with MHC class II molecules. The processing provides for exposure to the T lymphocytes of the immune system of epitopes which are buried in the interior of globular protein. Here we argue that autologous molecules (i.e., autoantigens) are also processed and that this applies to intracellular molecules as well as to plasma membrane proteins and tissues and serum proteins. The implication is that autoimmune T lymphocytes recognize fragments of self molecules in the context of MHC molecules and that autotolerance is toward these same epitopes.

Animals↗
PubMed2005

Determinations of B cell fate in immunity and autoimmunity.

A hallmark of thymus-dependent immunity is the generation of long-lived humoral immune responses. The production of long-lived memory B cells (B(mem)) and plasma cells (PCs) form the cellular basis for sustaining antibody-mediated immunity. During an immune response, the differentiation of B cells to become a B(mem) or PC occurs largely at the level of single cell fate decisions. Both of these cell populations acquire longevity as a result of antigen-specific, CD40-dependent, cognate interactions with helper T cells within germinal centers (GCs). In addition to these cellular elements that sustain humoral immunity, a novel GC-derived B cell that is a precursor to PCs has also been described. This cell is long-lived, highly proliferative, and terminally differentiates to end-stage cells within the bone marrow, and represents yet another cellular element that contributes to the long-lived nature of humoral immunity. Recent studies have shown that abnormalities in the B cell compartment of patients and mice with antibody-mediated autoimmune disease results from spontaneous GC responses, leading to the dysregulation in the development of PCs that produce pathogenic autoantibodies with altered homeostasis. The underlying cellular and molecular events that drive the loss of self-tolerance remain poorly understood. However, newer studies demonstrate that the strength of signaling via the B cell receptor, CD40 and BAFF receptors controls B cell fate decisions. Alterations in the magnitude of signaling through these molecules likely contribute to immune dysregulation that leads to the loss of self-tolerance. Understanding the processes of normal PC differentiation will provide strategic insights into identifying therapeutic targets for the treatment of antibody-mediated autoimmunity.

Animals↗
PubMed1998

The complexity of the B7-CD28/CTLA-4 costimulatory pathway.

There have been significant recent advances in our understanding of the role of the B7-CD28/CTLA-4 costimulatory pathway in T-cell activation and self-tolerance. Recent studies have begun to clarify how signaling through this pathway can influence cytokine production. The critical role for CTLA-4 in regulating T-cell activation and autoreactivity has been demonstrated, revealing a previously unsuspected means by which costimulation is involved in the maintenance and breakdown of self-tolerance. In vivo studies indicate the therapeutic potential of manipulating this important, but complex, immunoregulatory pathway.

Abatacept↗
PubMed2001

Immune responses to the HLA-A*0201-restricted epitopes of tyrosinase and glycoprotein 100 enable control of melanoma outgrowth in HLA-A*0201-transgenic mice.

Many of the Ags recognized by human melanoma-reactive CTL are derived from proteins that are also expressed in melanocytes. The possibility of self-tolerance to these epitopes has led to questions about their utility for antitumor immunotherapy. To investigate the issue, we established a preclinical model based on transgenic mice expressing a recombinant HLA-A*0201 molecule and B16 melanoma transfected to express this molecule. HLA-A*0201-restricted epitopes from the melanocyte differentiation proteins (MDP) tyrosinase and gp100 are expressed in both tumor cells and melanocytes, and the former is associated with self-tolerance. However, adoptive transfer of tyrosinase or gp100-reactive CTL developed from tolerant mice delayed tumor outgrowth, as did immunization with MDP peptide-pulsed dendritic cells. Protection was enhanced by the use of peptide ligands containing conservative substitutions that were cross-reactive with the original Ags. These data establish that CTL populations reactive against MDP-derived self-Ags can be activated to mount effective antitumor immunity and strongly support their continued development for tumor immunotherapy in humans.

Animals↗
PubMed1990

A role for clonal inactivation in T cell tolerance to Mls-1a.

Clonal deletion plays a major part in the maintenance of natural self-tolerance in both normal and transgenic mice. Self antigens that are expressed in the thymus result in the physical elimination of autoreactive thymocytes at a particular stage in their development. For example, the majority V beta 6- and V beta 8.1-bearing T cells that recognize the minor lymphocyte-stimulating antigen, Mls-1a (ref. 10) , are clonally deleted in the thymuses of normal mice and transgenic mice expressing Mls-1a (refs 2, 3, 9). In contrast, a very different mechanism of tolerance involving the functional inactivation, but not elimination, of autoreactive cells, termed clonal inactivation or clonal anergy, has been implicated in some experimentally manipulated systems of tolerance. To test further the mechanisms involved in self-tolerance, we have generated transgenic mice expressing a V beta 8.1 beta chain on greater than 95% of peripheral T cells and have tested tolerance to Mls-1a in these mice. Surprisingly, a significant fraction of the CD4+ peripheral cells that survived deletion were non-responsive in vitro to any stimulus tested. Naturally occurring tolerance to a self antigen expressed in the thymus can thus be mediated by clonal anergy, as well as by clonal deletion.

Animals↗
PubMed2000

The pathogenesis of autoimmunity in New Zealand mice.

OBJECTIVE: New Zealand mice were the first spontaneous animal model of human systemic lupus erythematosus (SLE). Since their initial discovery in 1959, studies of these mice have provided insights into the immunopathogenesis and genetics of lupus and have had a substantial impact on our understanding of autoimmunity. METHODS: We extensively reviewed published data for the past 40 years, including work in cellular immunology and molecular biology, to provide new information on the role of lymphoid subpopulations, cytokines, costimulatory molecules, apoptosis, and genetic susceptibility in the natural history of immunopathology in murine lupus. RESULTS: Genetic factors constitute the most important contribution to autoimmunity in New Zealand mice, and specific major susceptibility loci have been described. In addition, there is evidence for a pluripotent stem cell defect, which has implications for developmental and functional defects of T and B cells. The end result of these defects is a breakdown of self-tolerance and production of autoantibodies. Further studies will undoubtedly shape our understanding of this murine model and provide the basis for novel diagnostic and therapeutic approaches in humans. CONCLUSIONS: The advent of molecular biology, including the use of monoclonal antibody therapy in New Zealand mice, has been instrumental in our understanding of the loss of self-tolerance in SLE. Finally, identification of genetic susceptibility loci in the murine system has also led to important comparable studies in humans with SLE. RELEVANCE: The observations in New Zealand mice are of particular importance to systemic lupus erythematosus (SLE).

Animals↗
PubMed2000

The human leukocyte antigen complex and chronic ocular inflammatory disorders.

PURPOSE: To review the role of gene products from the human leukocyte antigen (HLA) complex in the normal functioning of the immune system, ocular inflammation, and models of autoimmunity. METHOD: A review of recently published reports. RESULTS: Many chronic ocular inflammatory diseases are associated with specific alleles of the HLA complex. Understanding how HLA gene products function normally provides clues to the mechanism of disease associations. In the thymus, these molecules control the shape of the developing T-cell repertoire, leading to self-tolerance. In the periphery, HLA molecules bind and present peptide fragments to T cells, leading to a variety of effector functions. Although effector functions are for the most part beneficial, models are reviewed in which peptide-HLA interactions lead to T-cell responses with pathologic consequences. Herpes stromal keratitis is an informative animal model highlighting the role of self-tolerance, infection, and molecular mimicry in the development of autoimmunity. CONCLUSIONS: Human leukocyte antigen gene products may be associated with chronic inflammatory disorders through the unique presentation of "disease-inducing" peptides or the development of a T-cell repertoire prone to autoreactivity and molecular mimicry.

Animals↗
PubMed2004

Covalent modification as a mechanism for the breakdown of immune tolerance to pyruvate dehydrogenase complex in the mouse.

The autoimmune liver disease primary biliary cirrhosis (PBC) is characterized by the breakdown of normal immune self tolerance to pyruvate dehydrogenase complex (PDC). How tolerance is broken to such a central and highly conserved self antigen in the initiation of autoimmunity remains unclear. One postulated mechanism is that reactivity arises to an altered form of self antigen with subsequent cross-reactivity to native self. In this murine study, we set out to examine whether sensitization with a covalently modified form of self PDC can give rise to the pattern of breakdown of B-cell and T-cell tolerance to self PDC seen in PBC patients. The notion that altered self can lead to tolerance breakdown was studied by sensitizing SJL/J mice with a covalently modified (biotinylated) preparation of self murine PDC (mP/O-B). Subsequently, antibody and T-cell reactivities to unmodified self mP/O were studied. Sensitization with mP/O-B elicited high-titre, high-affinity antibody responses reactive with both the mP/O-B immunogen and, importantly, native mP/O. In addition, significant MHC class II restricted splenic T-cell responses to native mP/O (i.e., true autoimmune responses) were seen in mP/O-B sensitized animals. The breakdown of T-cell self tolerance to mP/O was not seen in animals sensitized with irrelevant biotinylated antigens. In conclusion, this study provides evidence to support the concept that exposure to covalently modified self PDC can, in the correct proimmune environment, replicate the full breakdown of B-cell and T-cell immune tolerance to PDC seen in PBC. One potential etiological pathway in PBC therefore could be the breakdown of tolerance to self PDC occurring after exposure to self antigen covalently modified in the metabolically active environment of the liver.

Animals↗
PubMed1989

Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures.

The receptors found on most T lymphocytes bind to antigen presented on major histocompatibility complex proteins and consist of dimers of alpha- and beta-polypeptides associated with the invariant CD3 complex. A fully competent immune system requires a diverse array of T-cell antigen receptors (TCRs) with different specificities. This diversity is generated by rearrangement of TCR alpha- and beta-chain gene segments within the thymus where the receptors are first expressed. Any cells carrying self-reactive receptors must be eliminated, suppressed or inactivated so that destructive autoimmunity is avoided. Recently, compelling evidence has shown that one process involved in producing such self-tolerance is clonal deletion of autoreactive cells within the thymus by an as-yet-undefined mechanism. Here we show that engaging the CD3/TCR complex of immature mouse thymocytes with anti-CD3 antibodies produces DNA degradation and cell death through the endogenous pathway of apoptosis. Activation of this process in immature T cells by the binding of the TCR to self-antigens may therefore be the mechanism which produces clonal deletion and consequently self-tolerance.

Animals↗
PubMed1999

Reversal of immunodominance among autoantigenic T-cell epitopes.

Studies spanning several decades have revealed how the complex forces of antigen processing distinguish those epitopes of a protein that dominate the immune response from those that remain cryptic. Since foreign antigens and self-proteins are subjected to the same proteolytic pathways before presentation to the T-cell repertoire, it has long been assumed that they comply equally with the established rules of immunodominance. Nevertheless, the pathological determinants of some autoantigens appear ill-equipped for the dominant role they adopt, displaying features more befitting subdominant or cryptic epitopes, such as low affinity for their MHC restriction element. These findings may be reconciled by suggesting that, far from remaining sequestered during ontogeny, many classical autoantigens participate in the establishment of self-tolerance, the efficiency with which individual epitopes purge the T-cell repertoire being determined by the conventional rules of immunodominance: while those epitopes that are truly dominant induce profound non-responsiveness, those that are poorly presented may leave residual reactivity, manifest in the periphery as responses to epitopes that appear inappropriately dominant. Here we review recent evidence showing the process of self-tolerance to be uniquely responsible for the reversal of immunodominance which promotes such epitopes to an undeserved position of importance within the determinant hierarchy.

Animals↗
PubMed2006

Genetic vaccines against Ep-CAM break tolerance to self in a limited subset of subjects: initial identification of predictive biomarkers.

The epithelial cell adhesion molecule, Ep-CAM, has been historically considered a target of passive immunotherapy using monoclonal antibodies, and more recently, of a first Pox-vector-based cancer vaccine Phase I trial in colorectal cancer patients. To shed further light on the use of this antigen, we isolated the mouse and rhesus homologues of human Ep-CAM and explored different genetic vaccination modalities based on the use of adenoviral vectors as well as DNA electroporation (DNA-EP). Immune responses to Ep-CAM were measured by IFN-gamma ELISPOT and intracellular staining assays using overlapping sets of peptides covering the entire coding regions. We found the most powerful vaccination regimen to be constituted by DNA-EP-prime/Adeno-boost mixed-modality protocols. Vaccination in rhesus macaques resulted in breakage of immunological tolerance in a minority of cases. Similarly, a low frequency of responders was observed with the mouse Ep-CAM vaccine in outbred CD1 mice. When immunized CD1 mice were analyzed for MHC haplotype and TCR expression levels, we observed that immune responders all had the same q/q MHC class I haplotype and showed higher expression levels of the TCRVbeta4 and TCRVbeta8 T cell receptors. Our results underscore the current limitations in our capacity to induce efficient cancer vaccines against self antigens like Ep-CAM, but also represent a first effort to identify predictive biomarkers of response.

Adenoviridae↗
PubMed2002

Nondepleting anti-CD4 and soluble interleukin-1 receptor prevent autoimmune destruction of syngeneic islet grafts in diabetic NOD mice.

BACKGROUND: Successful islet transplantation in type 1 diabetes requires tolerance induction of both allo- and autoreactive T-cell responses. Monoclonal antibodies targeting the CD4 coreceptor on T-helper cells have been shown to be effective in this regard. In type 1 diabetes, there is some evidence to suggest that cytokines such as interleukin (IL)-1 may be involved in beta-cell destruction. The high glucose levels associated with type 1 diabetes are also known to be toxic to beta cells. METHOD: The tempo of T-cell and macrophage infiltration into syngeneic islets transplanted into diabetic nonobese diabetic (NOD) mice was examined by immunohistochemistry. We investigated the ability of a nondepleting anti-CD4 monoclonal antibody (YTS177) to induce tolerance to syngeneic islet grafts in female spontaneous diabetic NOD mice and in an adoptive transfer model of diabetes in NOD mice. The spontaneous model was used to test the effect on graft function of perioperative insulin therapy in mice treated with YTS177. The ability of soluble interleukin (sIL)-1 receptor (R) type II (sIL-1RII) to inhibit IL-1 effects in syngeneic islet transplants was also assessed. RESULTS: Cellular infiltration of CD3 cells and macrophages into the islet graft coincided with loss of graft function in untreated mice. Self-tolerance to beta cells was restored with YTS177, allowing long-term graft survival in a proportion of animals. The use of perioperative insulin therapy increased the number of successful grafts in spontaneously diabetic NOD mice treated with YTS177. The combination of YTS177 with sIL-1RII significantly improved the rates of graft survival compared with graft survival in YTS177-treated spontaneously diabetic NOD mice. CONCLUSIONS: Nondepleting anti-CD4 antibodies restore self tolerance to syngeneic islet transplants in diabetic NOD mice. Insulin therapy improves graft survival in mice treated with YTS177. Preventing the action of IL-1 greatly improves graft survival induced with YTS177.

Animals↗
PubMed1999

Prenatal immunotoxicant exposure and postnatal autoimmune disease.

Reports in humans and rodents indicate that immune development may be altered following perinatal exposure to immunotoxic compounds, including chemotherapeutics, corticosteroids, polycyclic hydrocarbons, and polyhalogenated hydrocarbons. Effects from such exposure may be more dramatic or persistent than following exposure during adult life. For example, prenatal exposure to the insecticide chlordane or to the polycyclic aromatic hydrocarbon benzo[(italic)a(/italic)]pyrene produces what appears to be lifelong immunosuppression in mice. Whether prenatal immunotoxicant exposure may predispose the organism to postnatal autoimmune disease remains largely unknown. In this regard, the therapeutic immunosuppressant cyclosporin A (CsA) crosses the placenta poorly. However, lethally irradiated rodents exposed to CsA postsyngeneic bone marrow transplant (i.e., during re-establishment of the immune system) develop T-cell-mediated autoimmune disease, suggesting this drug may produce a fundamental disruption in development of self-tolerance by T cells. The environmental contaminant 2,3,7, 8-tetrachlorodibenzo-(italic)p(/italic)-dioxin (TCDD) crosses the placenta and produces fetal thymic effects (italic)in vivo(/italic) similar to effects of CsA in fetal thymic organ culture, including inhibited thymocyte maturation and reduced expression of thymic major histocompatability complex class II molecules. These observations led to the suggestion that gestational exposure to TCDD may interfere with normal development of self-tolerance. Possibly supporting this hypothesis, when mice predisposed to development of autoimmune disease were treated with TCDD during gestation, postnatal autoimmunity was exacerbated. Similar results have been reported for mice exposed to diethylstilbestrol during development. These reports suggest that prenatal exposure to certain immunotoxicants may play a role in postnatal expression of autoimmunity.

Adult↗
PubMed1992

Is the establishing of tolerance to self obligatorily MHC restricted?

The prevailing paradigm used to interpret how T cells recognize antigen treats antigen processing as obligatory because the T cell antigen receptor complex can only detect antigen located in a "groove" found on MHC-encoded restricting elements. The vast majority of experimental systems used to analyze how T cells recognize antigen depend on induced T cells executing their effector functions, and it is agreed without exception that this event is MHC restricted. However, to date, the extrapolation of the obligatory MHC restriction of effector function to the level of the antigen-responsive T cell that makes the tolerance induction decision, depends not on experiment, but on theoretical constructs. The few experiments designed to test whether tolerance is MHC restricted are open to several interpretations, only one of which is consistent with the view that all antigen recognition events must be MHC restricted. If it can be shown that tolerance is not obligatorily MHC restricted, then the pillar of the prevailing paradigm will have fallen. The experiments described here throw into serious doubt the evidence that has been used to conclude that tolerance is obligatorily MHC restricted.

Animals↗
PubMed1990

Autoimmunity and the pathogenesis of glomerulonephritis.

Self-tolerance is maintained by: thymic influences on developing T cells; peripheral mechanisms that can tolerise post-thymic T cells; and to a variable extent the tolerisation of potentially autoreactive B cells. The presence of autoreactive T cells in normal individuals suggests that mechanisms to control the activity of such cells may be important. Failure of any of these processes may lead to autoimmunity. The relationship between glomerulonephritis and the mechanisms leading to breakdown of self-tolerance remains elusive. An important observation is that autoimmune diseases are strongly associated with particular products of the major histocompatibility complex (MHC). This association may reflect the intimate involvement of the MHC in thymic T cell education. Another explanation is that T cells only recognise antigens presented in the context of MHC molecules. Although there has been progress in identifying the targets recognised by autoantibodies in vasculitis and anti-GBM disease, nothing is known about the T cells involved. Despite our ignorance, therapy aimed specifically at the T cell can be effective. This approach is being supplemented by attempts to engage immunoregulatory mechanisms, such as idiotype-antiidiotype interactions. The hope is that such treatments, or combinations thereof, will allow a more focused suppression of the autoimmune response, in contrast to the non-specific (and therefore potentially dangerous) methods of immunosuppression available at present.

Autoantigens↗