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PubMed1989

Relative V beta transcript levels in thymus and peripheral lymphoid tissues from various mouse strains. Inverse correlation of I-E and Mls expression with relative abundance of several V beta transcripts in peripheral lymphoid tissues.

We have measured the relative levels of transcripts for 15 of the 22 known V beta gene segments. The level of transcripts for the highest and lowest expressed V beta gene segment differed by greater than 20-fold in the thymus and an even larger difference was observed in the periphery. The levels of expressions were unrelated to the order of the V beta genes on the chromosome. For most of the V beta gene segments, the relative transcript levels were the same in the thymus and periphery, suggesting that thymic selection in general does not act solely upon the V beta gene segment. One V beta gene segment in the BALB and B10 mice strains was an exception to this rule. V beta 5.2 expression in the periphery of BALB and B10 mice inversely correlated with the expression of the MHC class II molecule I-E. Five V beta gene segments had reduced transcript levels in the periphery of Mls-1a mice compared with their thymic levels or to the levels found in Mls-1b mice. The peripheral level of V beta 3 transcripts vary with MHC and Mls-2 haplotypes. The observation that certain V beta transcript levels are reduced in the periphery when compared with the thymus favors the hypothesis that self tolerance at the T cell level results in the elimination of self-reactive T cells, rather than paralysis by a block at some post-transcriptional step. Finally, the wide variability of V beta gene segment expression in the thymus suggests mechanisms exist to import an early bias to the repertoire. Whether this bias results from differential V beta segment rearrangement rates, differential V beta expression rates, or events occurring after TCR-alpha/beta expression on immature/nonmature thymocyte cell surfaces is yet to be determined.

Animals↗
PubMed2002

Peripheral deletion of autoreactive CD8 T cells by cross presentation of self-antigen occurs by a Bcl-2-inhibitable pathway mediated by Bim.

By transgenic expression of ovalbumin (OVA) as a model self antigen in the beta cells of the pancreas, we have shown that self tolerance can be maintained by the cross-presentation of this antigen on dendritic cells in the draining lymph nodes. Such cross-presentation causes initial activation of OVA-specific CD8 T cells, which proliferate but are ultimately deleted; a process referred to as cross-tolerance. Here, we investigated the molecular basis of cross-tolerance. Deletion of CD8 T cells was prevented by overexpression of Bcl-2, indicating that cross-tolerance was mediated by a Bcl-2 inhibitable pathway. Recently, Bim, a pro-apoptotic Bcl-2 family member whose function can be inhibited by Bcl-2, was found to play a critical role in the deletion of autoreactive thymocytes, leading us to examine its role in cross-tolerance. Bim-deficient T cells were not deleted in response to cross-presented self-antigen, strongly implicating Bim as the pro-apoptotic mediator of cross-tolerance.

Animals↗
PubMed1989

Split tolerance in nude mice transplanted with 2'-deoxyguanosine-treated allogeneic thymus lobes.

To elucidate the acquisition of self tolerance in the thymus, full-allogeneic thymic chimeras were constructed. Athymic C3H and BALB/c nude mice were reconstituted with the thymic lobes of BALB/c and B10.BR fetuses, respectively, that were organ cultured for 5 days in the presence of 2'-deoxyguanosine. T cells in these chimeras were tolerized to the host MHC in both MLR and CTL assays. In contrast, T cells in the chimeras exhibited split tolerance for the thymic MHC haplotype. CTL specific for class I MHC of the thymic haplotype were generated not only from the peripheral T cells of the chimeras but also from thymocytes re-populated in the engrafted thymic lobes. However, T cells in these chimeras responded poorly to the class II MHC of the thymic haplotype in a standard MLR assay. In a syngeneic MLR culture upon stimulation with enriched APC of the thymic haplotype, only 22 to 48% of the responses were mediated by CD4+ cells, and proliferations of CD4- cells were prominent. There were no haplotype-specific suppressor cells detected which would cause the unresponsiveness to the thymic class II MHC. These results indicated that the thymic lobes treated with 2'-deoxyguanosine were defective in the ability to induce the transplantation tolerance for the class I MHC expressed on the thymus, although the same thymic lobes were able to induce the transplantation tolerance for the thymic class II MHC.

Animals↗
PubMed2004

Central tolerance to self-antigen expressed by cortical epithelial cells.

The exposure of developing thymocytes to high-affinity self-Ag results in T cell tolerance. A predominant mechanism for this is clonal deletion; though receptor editing, anergy induction, and positive selection of regulatory T cells have also been described. It is unclear what signals are involved in determining different tolerance mechanisms. In particular, OT-I mice displayed receptor editing when the high-affinity self-Ag was expressed in cortical epithelial cells (cEC) using the human keratin 14 promoter. To test the hypothesis that receptor editing is a consequence of a unique instruction given by cEC presenting self-Ag, we created mice expressing the 2C and HY ligands under control of the keratin 14 promoter. Alternatively, we studied the fate of developing T cells in OT-I mice where Ag was presented by all thymic APC. Surprisingly, we found that the tolerance mechanism was not influenced by the APC subset involved in presentation. Clonal deletion was observed in 2C and HY models even when Ag was presented only by cEC; and receptor editing was observed in OT-I mice even when Ag was presented by all thymic APC. These results suggest that different TCRs show intrinsic differences in thymic tolerance mechanism.

Animals↗
PubMed1980

Allogeneic tolerance in embryo aggregation mouse chimeras studied by mixed lymphocyte culture and cell-mediated lympholysis.

Tolerance in embryo aggregation (EA) mouse chimeras was investigated using mixed lymphocyte culture (MLC) reaction and cell-mediated lympholysis (CML). In most cases, spleen or lymph node cells from EA chimeras were specifically unresponsive toward their parental cells in both MLC and CML. There was no evidence to support the involvement of "serum-blocking factors" or suppressor cells under these experimental conditions. There was, however, an exceptional chimera in which cytotoxic T cell percursors reactive against one parental cell may have been present. We argue for classical clonal elimination being the primary mechanism for tolerance in EA chimeras and discuss a role of suppressor mechanisms for self-tolerance.

Animals↗
PubMed1988

Tolerogenic activity of polymerized type II collagen in preventing collagen-induced arthritis in rats.

Rats were exposed parenterally or pergastrically to polymerized type II collagen (POLCII) and became resistant to the subsequent induction of disease with arthritogenic type II collagen (CII) administered intradermally in Freund's incomplete adjuvant (FIA). POLCII was prepared by cross-linking native soluble arthritogenic CII, from bovine nasal septal cartilage, with glutaraldehyde. POLCII injected intradermally in FIA did not induce arthritis. Animals treated in this manner were resistant for a period of at least 100 days to induced disease. The change in the properties of the CII from an arthritogen to a tolerogen was related to the amount of glutaraldehyde (used to polymerize the CII) which was assumed to control the extent of cross-linking of the CII. Highly cross-linked POLCII administered pergastrically, like soluble CII, was not arthritogenic but was tolerogenic, inducing a state of unresponsiveness to a challenge with arthritogenic CII. In general serum anti-CII antibody levels were higher in arthritic than in tolerized non-arthritic rats. It is concluded that the breaking of self-tolerance to CII depends upon its physical state. When polymerized and insoluble, a form analogous to that in which it exists naturally, it is tolerogenic.

Animals↗
PubMed1993

T cell repertoire and autoimmune diseases.

Self-reactivity and autoimmunity are processes related to the breakage of self-tolerance that can be distinguished by their different clinical outcome and are widely accepted cornerstones of immunology. The finding that several potentially autoaggressive cells contribute to the repertoire of healthy individuals has stimulated a great deal of experimental work aimed at understanding the mechanisms that prevent autoimmune pathology. In this review we will consider the basic principles, and our present knowledge of the rules that preside over the interplay of the immune system with self-components. One viewpoint stresses the importance of major histocompatibility complex (MHC) and non-MHC genes in determining genetic predisposition to develop autoimmune phenomena. At a different level there is a strong interest in understanding the mechanisms of processing and presentation of self antigens, especially during ontogeny. Another topic of major interest concerns the interaction between MHC genes and the T cell receptor (TcR) complex as well as the identification of TcR V genes that are preferentially expressed by autoimmune T cells. All of these aspects are evaluated in the context of tolerance based on deletion and anergy. Finally we will propose a general model of autoimmunity based on the most recent findings concerning the biological activity of exogenous superantigens.

Animals↗
PubMed1991

B-cell selection and tolerance.

The B-lymphocyte repertoire can be divided into a primary repertoire of virgin B cells and a secondary repertoire of antigenically experienced cells. Self-tolerance requires that neither of these repertoires contains potentially active cells capable of high-affinity, anti-self antibody production. Recent work has proven that both the primary and the secondary repertoire can be functionally purged, and this mechanism may involve failure of appearance of anti-self clonotypes (clonal abortion) or defects in activation (clonal anergy).

Animals↗
PubMed1988

Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes.

The mechanism of self-tolerance is studied in T-cell-receptor transgenic mice expressing a receptor in many of their T cells for the male (H-Y) antigen in the context of class I H-2Db MHC antigens. Autospecific T cells are deleted in male mice. The deletion affects only transgene-expressing cells with a relatively high surface-density of CD8 molecules, including nonmature CD4+ CD8+ thymocytes, and is not caused by anti-idiotype cells.

Animals↗
PubMed2000

Autoimmunity and primary biliary cirrhosis.

The history of primary biliary cirrhosis (PBC) began in 1851, with autoimmunity introduced in 1958 and expanded from the 1960s on. In PBC, autoantibodies are present to mitochondria-located antigens (AMA) and to nuclear-located antigens (ANA). The AMA react with E2 subunits of three members of the 2-oxoacid dehydrogenase complex family, but most frequently with pyruvate dehydrogenase complex (PDC); the inner lipoyl domain of PDC-E2 contains a major B- and T-cell epitope. The ANA react with three nuclear components, centromeric proteins, nuclear dot proteins and nuclear pore complex. Autoimmune diseases including PBC reflect a failure in mechanisms of self-tolerance which is developed in central lymphoid tissues in embryonic life by deletion of self-reactive lymphocytes, and maintained in peripheral tissues in post-natal life by regulatory processes. Primary biliary cirrhosis has not yet been identified with failure in any one particular tolerance mechanism. Genetic influences are revealed by familial occurrences and by associations with HLA alleles, and environmental influences by epidemiological data. A lead to pathogenesis is the accumulation uniquely in PBC of PDC-E2-like material at the plasma membrance of biliary epithelial cells (BECs). Although the origin of this accumulation of PDC-E2 at the surface of BECs is uncertain, it provides a credible 'tissue-specific' target for an autoimmune attack by T and B lymphocytes at the site of the actual pathology.

Autoantibodies↗
PubMed1997

Antigen presentation in uveitis.

Experimental autoimmune uveoretinits (EAU) is not only a valuable model for human inflammatory eye diseases, it is also a useful system for studying many aspects of immunobiology. One such aspect is self/non-self discrimination, the ability of the immune system to tolerate self molecules while responding aggressively to foreign antigens. Our laboratory has used EAU to investigate the mechanisms of T cell tolerance to retinal S-antigen (S-Ag). Several mechanisms have been proposed to maintain T cell tolerance to autoantigens, including clonal deletion and clonal anergy. As immunisation with S-Ag or pathogenic peptides activates uveitogenic T cells, tolerance to this autoantigen cannot be due to clonal deletion. Nevertheless, tolerance acts to keep these existing autoreactive T cells in a naive, or innocuous state. Here we suggest a novel mechanism--low-affinity occupancy of the autoantigen-specific T cell receptor (TCR) by self-antigen--that may act in concert with the well-known mechanisms to maintain tolerance to S-Ag in the LEW rat. This model differs from clonal anergy in that the missing antigen-presenting cell (APC) activity is not a co-stimulatory function but a TCR co-ligand that increases the avidity of the interaction between the TCR and its peptide-major histocompatibility complex (MHC) ligand. In the absence of this co-ligand only partial signals are generated through the TCR, leading to incomplete T cell activation. This model was deduced from experiments with T cell lines and hybridomas specific for S-Ag, which showed that: (1) autoreactive T cells required a novel APC function, (2) this novel function was necessary to provide complete TCR engagement, and (3) activation of autoreactive T cells was restricted to specific APC.

Animals↗
PubMed1993

Mechanisms of autoimmunity in type I diabetes.

The work presented in this review suggests that in human and murine type I diabetes, defective MHC class I expression on APC is linked to autoimmunity. The defect in self-antigen presentation is present on prediabetic and diabetic APC, and this presumably delivers abnormal or lack of signals to T cells to allow self tolerance. Since most autoimmune diseases have strong genetic linkage to MHC class II region, our recent results additionally demonstrating low MHC class I expression on lymphoid cells in a diversity of autoimmune diseases (hypothyroidism, rheumatoid arthritis, lupus, etc.) suggest that this pathway of abnormal class I presentation of self epitopes may be important for tolerance to many tissue-specific antigens (40). Certainly, the unanswered genetic questions will address the role of the specific genes controlling self-antigen presentation through MHC class I followed by T-cell education to self.

Animals↗
PubMed2001

Adoptive transfer enables tumor rejection targeted against a self-antigen without the induction of autoimmunity.

We have previously described a tumor model in which the influenza hemagglutinin protein (HA) expressed on the BALB/c-derived MT901 tumor line serves as an immunization-dependent tumor rejection antigen in normal syngeneic mice. Although the HA antigen in this model is clearly foreign to normal BALB/c mice, many tumor antigens recognized by T cells in humans and mice are nonmutated antigens that are expressed on normal tissues as well as on the tumor cells, thereby raising issues of self-tolerance and autoimmunity in attempts to use such antigens therapeutically. To examine these issues, we have applied our tumor model to syngeneic mice that broadly express HA at low levels as a "self"-transgene. Unlike the situation in normal BALB/c mice, immunization of HA-transgenic mice did not result in tumor protection nor did it generate cytotoxic T cell or IgG responses against the HA self-antigen. However, if immunization of HA-transgenic mice was preceded by adoptive transfer of spleen and lymph node cells from normal untreated BALB/c mice, then HA-specific tumor protective immune responses were generated. Despite the self-nature of the HA antigen, no obvious manifestations of autoimmunity were observed. The immunity established in the transgenic mice was notably different from that observed in normal mice in that it was considerably more transient and required CD4 T cells for both successful immunization and subsequent tumor protection, qualities that were not associated with the immunity established in normal BALB/c mice. Collectively our results suggest that transferred cells can be transiently and selectively directed against a tumor-expressed self-antigen before returning to a tolerant state.

Animals↗
PubMed1980

Tolerance inducibility and the elicitation of autoantibodies by LPS in aged NZB mice.

Correlation between tolerance inducibility to human IgG and the elicitation of anti-erythrocyte autoantibodies by LPS was investigated in NZB mice. At first, tolerance inducibility to human IgG was examined in various ages of the mice. Straight relationship was found between the age of mice and tolerance inducibility; the older mice became, the more difficult it became to induce tolerance. This age-related change was also shown at the level of B lymphocytes. When LPS was injected into tolerogen-resistant, aged mice, anti-erythrocyte autoantibodies were elicited. On the other hand, autoantibodies were never detected in younger NZB mice or other strains of comparable aged mice. From these results, it is assumed that similar mechanisms are operating in the escape from self-tolerance and the resistance to tolerance to heterologous antigens, thus self-reactive B lymphocytes gradually appear with the age of NZB nice in which the resistance to tolerance induction become apparent.

Aging↗
PubMed1977

Tolerance in differentiating B lymphocytes.

These experiments demonstrate that the response of B lymphocytes to particulate antigen in vivo can depend on their stage of differentiation: B lymphocytes differentiating from stem cells were rendered tolerant, while mature B lymphocytes were primed under the same conditions. Lethally irradiated mice of one allotype were repopulated with 13-15 day fetal liver cells from congenic mice bearing another allotype and the effect of antigen on the emergence of responsive B cells determined. B cells, descended from the fetal liver inoculum (identified by their allotype) produced an antibody response to antigen in the presence of additional T cells, 15 days after transfer. Such a response could be prevented by injecting the recipient with alum-precipitated antigen (but not with deaggregated antigen) shortly after irradiation and reconstitution. This unresponsive state was specific and independent of afferent suppressor mechanisms. Mature B cells, on the other hand, were shown to be primed by alum precipitated antigen in irradiated reconstituted hosts. It was concluded that a fundamental difference exists between the responsiveness of mature and differentiating B lymphocytes. Tolerance in differentiating B lymphocytes is discussed in relation to the acquisition of self-tolerance.

Animals↗
PubMed1989

Does T-cell tolerance require a dedicated antigen-presenting cell?

Almost 30 years ago Burnet proposed that the immune system maintained self-tolerance by deleting autoreactive lymphocytes. Recently it has become clear that for T cells this step occurs in the thymus, where developing T cells first express their antigen-specific receptors. Here a T-cell which encounters its antigen disappears--if it is not dead, it at least stops expressing its receptors. In the periphery by contrast, encounter with antigen leads to activation and proliferation of the responding T-cell. There are two possible explanations for this difference. Either the antigen-presenting cells in the thymus are different from those in the periphery and instead of producing positive signals they directly or indirectly kill the thymocytes; or the T cells themselves are different, and like immature B cells, may die after encounter with antigen. We tested the first possibility and found that dendritic cells from spleen, which are the most potent activators of mature T cells, are also the most potent inactivators of young developing T cells. Thus it is not the antigen-presenting cell which determines whether a T-cell responds or dies, but the T-cell itself or its thymic environment.

Animals↗
PubMed1977

Ontogeny of B-lymphocyte function. III. In vivo and in vitro studies on the ease of tolerance induction in B lymphocytes from fetal, neonatal, and adult mice.

The ease of tolerance induction in B lymphocytes from fetal, neonatal, and adult mice was studied in vivo, in a cell transfer system, and in vitro. Three different tolerogens were used: ultracentrifuged BGG, DNP(6)-D-GL, and ultracentrifuged DNP(22)-BGG. Irradiated thymectomized mice were reconstituted with B cells from fetal or neonatal liver or adult spleen or bone marrow. The mice were injected with tolerogen 1 day later. They were given normal thymus cells and challenged with either BGG or DNP(44)-BGG between 4 and 14 days after tolerance induction. With BGG no difference in ease of B-cell tolerance induction was observed in mice reconstituted with B cells from 17-day fetal liver, neonatal liver, 8- day-old spleen, adult spleen, or adult bone marrow. B cells from 14-day fetal donors are relatively resistant to tolerance induction. In contrast, with DNP(6)-D-GL and DNP(22)-BGG B cells from neonatal donors were clearly more susceptible to tolerance induction than were B cells from adult donors. Comparable results were obtained in studies on tolerance induction in vitro. Neonatal B cells were more susceptible than adult B cells to tolerance induction upon culture with DNP(6)-D-GL or DNP(22)-BGG. However, neonatal and adult B cells were identical with respect to ease of tolerance induction in vitro with deaggregated BGG. The results suggest that there are multiple mechanisms for B-cell tolerance induction. Immature B cells appear to be more susceptible to tolerance induction by some mechanisms but not by others. It is suggested that immature B cells are more susceptible to tolerance induction with moderately polyvalent antigens such as hapten-carrier conjugates. With antigens like BGG which do not haverepeated epitopes no difference between mature and fetal B cells in regard to ease of tolerance induction is observed. These observations raise questions about the importance of relative ease of tolerance induction in immature B cells as a mechanism controlling the normal induction of self tolerance.

Animals↗
PubMed1994

Split tolerance in chimeric GVH mice.

The i.v. inoculation of parental spleen cells into unirradiated adult F1 hybrid mice results in a graft-versus-host reaction (GVHR). In the strain combination B10D2 --> (B10.BRx B10.D2) F1, this reaction is associated with thymic injury and transient but profound cellular immune deficiency. We further analysed the immune status of these mice 60 days after GVHR induction. Phenotypic studies of spleen cells showed that these mice were repopulated with parental lymphocytes resulting in a high degree of chimerism (85%). At this time, the mice looked healthy and recovered a normal cytotoxic T cell response (CTL) against allogeneic cells. GVH chimeric splenocytes were unresponsive against F1 hybrid cells in mixed lymphocyte culture (MLC), but exhibited anti-F1 CTL reactivity. We also analysed the anti-F1 reactivity of these mice in vivo. GVH chimeric splenocytes were unable to induce GVHR after injection into a new F1 hybrid and F1 GVH mice specifically rejected F1 bone marrow (BM) cells after lethal irradiation. Grafting a neonatal parental thymus prevented the rejection of F1 BM cells and restored CTL alloreactivity. It is concluded that the chimeric state induced by GVHR is associated with a split tolerance and that a radiosensitive thymic-dependent mechanism is involved in maintaining self-tolerance in these mice.

Animals↗