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Results for “Self Tolerance”

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PubMed2002

Gram-negative flagellin-induced self-tolerance is associated with a block in interleukin-1 receptor-associated kinase release from toll-like receptor 5.

Flagellin from a number of Gram-negative bacteria induces cytokine and nitric oxide production by inflammatory cell types. In view of the evidence that flagellin responsiveness is subject to modulation, we explored the possibilities that a prior exposure to flagellin might result in a state of reduced flagellin responsiveness or tolerance and that lipopolysaccharide (LPS) and flagellin may induce a state of cross-tolerance to each other. Our results demonstrate that a prior exposure to flagellin results in a subsequent state of flagellin tolerance in human monocytes, THP1 cells, Jurkat cells, and COS-1 cells. Tolerance occurs within 2 h after addition of flagellin and does not require protein synthesis. Flagellin did not induce tolerance to LPS in monocytes and THP1 cells; however, LPS treatment of monocytes and THP1 cells resulted in a state of flagellin cross-tolerance. Flagellin-induced self-tolerance is not the result of a decrease in the steady-state level of toll-like receptor 5 (TLR5) or interleukin-1 receptor associated kinase (IRAK), but it is associated with a block in the release of IRAK from the TLR5 complex in flagellin-tolerant cells. Release is essential for IRAK activity because the TLR5-associated IRAK lacks kinase activity. LPS-induced cross-tolerance to flagellin is also associated with a block in IRAK release from TLR5. These results provide evidence for a novel mechanism of TLR signaling control.

Animals↗
PubMed1999

Linkage of immune self-tolerance with the positive selection of T cells.

Development and maturation of antigen-specific T cells take place in the thymus in a process dependent on recognition by the T cell antigen receptor (TCR) of endogenous self-peptides presented by several types of specialized stromal cells. Paradoxically, emerging T cells are not self-reactive, and it is commonly believed that deletion of high avidity autoreactive T cells is the principal mechanism for establishing self-tolerance. However, there is increasing evidence that the positive selection of T cells on self-peptides presented by thymic cortical epithelial cells must be linked with a process that prevents their subsequent activation when the same self-peptides are encountered in the periphery. Consequently, a higher activation threshold is established that can be overcome only with ligands of higher affinity, which would normally be foreign peptides. The molecular basis for this increase in activation threshold is unknown, but observations on differential signaling by peptide analogs, on increased TCR expression during T cell maturation and on energy induction in the absence of costimulation provide promising leads. Linkage of self-tolerance with positive selection is a simple and evolutionary sound explanation for self/non-self discrimination and offers a framework for understanding systemic autoimmunity.

Adaptation, Physiological↗
PubMed2005

Dependence of self-tolerance on TRAF6-directed development of thymic stroma.

The microenvironments of the thymus are generated by thymic epithelial cells (TECs) and are essential for inducing immune self-tolerance or developing T cells. However, the molecular mechanisms that underlie the differentiation of TECs and thymic compartmentalization are not fully understood. Here we show that deficiency in the tumor necrosis factor receptor-associated factor (TRAF) 6 results in disorganized distribution of medullary TECs (mTECs) and the absence of mature mTECs. Engraftment of thymic stroma of TRAF6(-/-) embryos into athymic nude mice induced autoimmunity. Thus, TRAF6 directs the development of thymic stroma and represents a critical point of regulation for self-tolerance and autoimmunity.

Animals↗
PubMed2002

Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance.

CD25(+)CD4(+) regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance. We show here that glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR, also known as TNFRSF18)--a member of the tumor necrosis factor-nerve growth factor (TNF-NGF) receptor gene superfamily--is predominantly expressed on CD25(+)CD4(+) T cells and on CD25(+)CD4(+)CD8(-) thymocytes in normal naïve mice. We found that stimulation of GITR abrogated CD25(+)CD4(+) T cell-mediated suppression. In addition, removal of GITR-expressing T cells or administration of a monoclonal antibody to GITR produced organ-specific autoimmune disease in otherwise normal mice. Thus, GITR plays a key role in dominant immunological self-tolerance maintained by CD25(+)CD4(+) regulatory T cells and could be a suitable molecular target for preventing or treating autoimmune disease.

Animals↗
PubMed1991

Induction of self-tolerance in T cells but not B cells of transgenic mice expressing little self antigen.

Self-tolerance to a transgene-encoded protein, hen egg lysozyme, was examined in the T and B cell repertoires of a series of lines of transgenic mice that expressed different serum concentrations of soluble lysozyme. T cells were tolerant in all lines in which lysozyme was expressed irrespective of the antigen concentration, whereas B cell tolerance did not occur when the serum lysozyme concentration was less than 1.5 nanograms per milliliter (0.1 nM). Induction of elevated transgene expression could restore B cell tolerance. These findings support the hypothesis that autoimmune disease may in some instances arise through a bypass of T cell tolerance.

Animals↗
PubMed1989

Peripheral self-tolerance and autoimmunity: the protective role of expression of class II major histocompatibility antigens on non-lymphoid cells.

Immunologic self-tolerance is achieved mainly during development by clonal deletion in the thymus of T lymphocytes with receptors specific for self-antigens and with associated T-cell markers CD4/CD8. However, T cells expressing a low level of these markers are allowed into the periphery still bearing their autospecific receptors. Such clonal deletion, induced by cells bearing the class II antigens coded for by major histocompatibility complex (MHC) in the thymus, does not remove all autoreactive T cells specific for antigens of differentiated tissue expressed extrathymically. However, these autoreactive T cells are silent in the periphery. Peripheral non-lymphoid cells (e.g., endocrine cells) can induce antigen-specific unresponsiveness in T cells and can specifically suppress production of autoantibody against their antigens when the non-lymphoid cells express class II MHC antigens on their surface. This class II MHC expression is induced by interferon-gamma produced by T cells as a result of various immune responses, such as autoimmune reaction. Thus, the expression of class II MHC antigens on non-lymphoid cells may serve as a peripheral mechanism for the induction and maintenance of self-tolerance in autoreactive T cells that escape negative selection in the thymus or that are specific for extrathymic tissue antigens, in a fail-safe mechanism against autoimmunity. Some autoimmune diseases, especially organ-specific ones, might be caused by a defect in this fail-safe mechanism.

Autoimmune Diseases↗
PubMed1990

Flexibility of the T cell repertoire. Self tolerance causes a shift of T cell receptor gene usage in response to insulin.

Bovine insulin(BI)-specific I-Ab-restricted T cell clones have been characterized for fine specificity and TCR gene usage. We have demonstrated that mouse strains carrying H-2b on three different genetic backgrounds (C57BL, BALB, and 129) rearrange and express the V beta 6 gene in a large proportion (36%) of insulin-specific clones. In these strains, the non-MHC background did not seem to influence TCR gene usage in response to BI. The V beta 6+ clones appeared to be selected by the antigen. In contrast, no V beta 6+ clones could be isolated from (B6 x DBA/2)F1 mice, where V beta 6+ (and V beta 8.1+) T cells are deleted by self tolerance to Mls-1a. Thus, although a small proportion of residual V beta 6+ cells had been demonstrated in Mls-1a mice, these cells could not be retrieved in a response that uses V beta 6 predominantly. In functional terms, therefore, the deletion of V beta 6 by self tolerance appears to be complete. Instead of V beta 6, the majority (up to 60%) of I-Ab- as well as I-Ad-restricted insulin-specific clones from the (B6 x DBA/2)F1 mice expressed V beta 8.2 and V beta 8.3. This shift of gene usage was not accompanied by any detectable change in the fine specificity pattern of response. Thus, in the insulin-specific response, the flexibility of T cell repertoire fully compensates for deletions caused by self tolerance.

Animals↗
PubMed2006

Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease.

Naturally arising CD25+ CD4+ regulatory T (Treg) cells, most of which are produced by the normal thymus as a functionally mature T-cell subpopulation, play key roles in the maintenance of immunologic self-tolerance and negative control of a variety of physiological and pathological immune responses. Natural Tregs specifically express Foxp3, a transcription factor that plays a critical role in their development and function. Complete depletion of Foxp3-expressing natural Tregs, whether they are CD25+ or CD25-, activates even weak or rare self-reactive T-cell clones, inducing severe and widespread autoimmune/inflammatory diseases. Natural Tregs are highly dependent on exogenously provided interleukin (IL)-2 for their survival in the periphery. In addition to Foxp3 and IL-2/IL-2 receptor, deficiency or functional alteration of other molecules, expressed by T cells or non-T cells, may affect the development/function of Tregs or self-reactive T cells, or both, and consequently tip the peripheral balance between the two populations toward autoimmunity. Elucidation of the molecular and cellular basis of this Treg-mediated active maintenance of self-tolerance will facilitate both our understanding of the pathogenetic mechanism of autoimmune disease and the development of novel methods of autoimmune disease prevention and treatment via enhancing and re-establishing Treg-mediated dominant control over self-reactive T cells.

Animals↗
PubMedDate not supplied

Regulatory T cells in immunologic self-tolerance and autoimmune disease.

Naturally arising CD25+ CD4+ regulatory T cells play key roles in the maintenance of immunologic self-tolerance and negative control of various immune responses. The majority, if not all, of them are produced by the normal thymus as a functionally distinct T-cell subpopulation, and their generation is in part developmentally controlled. Genetic abnormality in the development and function of this population can indeed be a cause of autoimmune disease, immunopathology, and allergy in humans. This regulatory population can be exploited to prevent and treat autoimmune disease by strengthening and reestablishing immunologic self-tolerance.

Antigens, CD↗
PubMedDate not supplied

Acquisition of self-tolerance in T cells is achieved by different mechanisms, operating both inside and outside the thymus.

During the past 3 years, considerable progress has been generated in understanding the mechanisms by which developing T cells acquire tolerance for self-antigens. Clonal deletion of T cells with self-reactive receptors for certain antigens expressed in the thymus was the first process to be identified as a major mechanism for generating tolerance in thymocytes. When this process fails, nondeletional mechanisms for acquisition of tolerance to self-antigens are employed. If the molecular mechanisms underlying these events are to be understood, it is crucial to identify to which extent these alternate forms of tolerance induction operate at different stages of T cells development. This article reviews where and how the tolerant state is achieved at different stages of T cell development.

Animals↗
PubMed1994

Gld and lpr mice: single gene mutant models for failed self tolerance.

Mice homozygous for the gld or lpr mutations develop autoimmunity, and a lymphoproliferative disorder involving accumulation of huge numbers of unusual CD4-CD8-TCR alpha beta lo T cells. Here we review our past work with gld mice, and attempt to explain lymphoproliferation in terms of current models of T cell maturation and self-tolerance induction. The availability of molecular probes to the gene products of lpr and gld should shortly lead to a better understanding of the acquisition of self tolerance during T cell maturation and of autoimmunity.

Animals↗
PubMed2003

The role of regulatory T cells in controlling immunologic self-tolerance.

Accumulating evidence indicates that T cell-mediated dominant control of self-reactive T cells contributes to the maintenance of immunologic self-tolerance and its alternation may lead to development of autoimmune disease. Efforts to delineate such a regulatory T cell population have revealed that CD25+ cells within the CD4+ population in normal naive animals including humans possess the regulatory activity. The CD25+CD4+ regulatory T cells are produced by the normal thymus as a functionally distinct subpopulation of T cells. They play critical roles not only in preventing autoimmunity but also in controlling various immune reactions.

Animals↗
PubMed1999

Escape from self-tolerance leads to neonatal insulin-dependent diabetes mellitus.

Double transgenic (dTg) mice expressing the hemagglutinin (HA) of influenza virus under the insulin promoter and the TCR specific for the immunodominant CD4 T cell epitope of HA (HA110-120) develop insulin-dependent diabetes mellitus (IDDM). In order to gain information on the breaking down of neonatal self-tolerance we studied the occurrence of IDDM after birth. Our results showed that newborn mice develop fulminant IDDM characterized by occurrence of insulitis as early as 3 days after birth, followed by hyperglycemia by 7 days, and significant hypoinsulinemia by 28 days. The neonatal breakdown of self-tolerance of T cells positively selected in the thymus is supported by the facts that: (i) peripheral HA110-120 specific T cells from neonates are fully functional and proliferated upon stimulation with the nominal peptide, and (ii) peptide-specific T cells were accumulated in the pancreas of dTg mice as early as 3 days after birth. Our results demonstrate that diabetes occurring in young dTg mice is due to early activation of self-reactive T cells immediately after birth. Accumulation of specific T cells in the target organ leads to destruction of pancreatic beta-cells and IDDM. These mice may provide a useful model to evaluate new strategies for the prevention of diabetes.

Animals↗
PubMed1992

Immune regulation in self tolerance: functional elimination of a self-reactive, counterregulatory CD8+ T lymphocyte circuit by neonatal transfer of encephalitogenic CD4+ T cells lines.

Transfer of encephalitogenic, CD4+ T lymphocyte lines into syngeneic adult Lewis rats not only leads to the development of experimental autoimmune encephalomyelitis (EAE), but, in addition, to the expansion of counterregulatory, CD8+ T lymphocyte clones which are able to lyse specifically the encephalitogenic T cells in vitro and to neutralize their encephalitogenic capacity in vivo. In striking contrast, in neonatal rats, which still lack myelin (autoantigens), injection of the same encephalitogenic lines neither mediates EAE, nor confers protection in later life against the myelin-specific T cells. In fact, this treatment results in the life-long functional elimination of counterregulatory, clonotypic CD8+ T lymphocytes, which cannot even be reinduced by repeated injections of the relevant CD4+ T line. These data seem to point to a self-protective T cell control mechanism which is developed within the immune system prior to, and thus independent of the appearance of the appropriate self antigen.

Animals↗
PubMed1994

Tissue-specific suppressor T cells involved in self-tolerance are activated extrathymically by self-antigens.

Autoimmune prostatitis developed spontaneously in (C57BL/6N x A/J)F1 (B6A) mice, when thymectomy (Tx) was conducted on day 3 after birth (Tx-3). The lesion could be prevented by a single injection of CD4+ spleen cells (4 x 10(6)) from normal males, but not from normal females or newborn orchidectomized (Orx-0) mice. However, when spleen cells were obtained from Orx-0 mice that had received a dihydrotestosterone (DHT) pellet when adult to develop a mature prostate, prostatitis could be prevented, suggesting that immune tolerance to prostate antigen(s) is maintained by a CD4+ tissue-specific suppressor T cell (Ts) population(s), which is activated by a specific autoantigen(s) in the mature prostate. The result that even CD4+ cells from Orx-0 mice that were thymectomized as adults and treated thereafter with DHT were effective for prevention of prostatitis suggests that activation of this Ts population takes place in the peripheral lymphoid organs, and that it maintains peripheral tolerance to autoantigen in the prostate of these mice and probably also in normal mice.

Animals↗
PubMed1998

Beta2-microglobulin-deficient NK cells show increased sensitivity to MHC class I-mediated inhibition, but self tolerance does not depend upon target cell expression of H-2Kb and Db heavy chains.

Mice lacking beta2-microglobulin (beta2m- mice) express greatly reduced levels of MHC class I molecules, and cells from beta2m- mice are therefore highly sensitive to NK cells. However, NK cells from beta2m- mice fail to kill beta2m- normal cells, showing that they are self tolerant. In a first attempt to understand better the basis of this tolerance, we have analyzed more extensively the target cell specificity of beta2m- NK cells. In a comparison between several MHC class I-deficient and positive target cell pairs for sensitivity to beta2m- NK cells, we made the following observations: First, beta2m- NK cells displayed a close to normal ability to kill a panel of MHC class I-deficient tumor cells, despite their nonresponsiveness to beta2m- concanavalin A (Con A)-activated T cell blasts. Secondly, beta2m- NK cells were highly sensitive to MHC class I-mediated inhibition, in fact more so than beta2m+ NK cells. Thirdly beta2m- NK cells were not only tolerant to beta2m- Con A blasts but also to Con A blasts from H-2Kb-/Db- double deficient mice in vitro. We conclude that NK cell tolerance against MHC class I-deficient targets is restricted to nontransformed cells and independent of target cell expression of MHC class I free heavy chains. The enhanced ability of beta2m- NK cells to distinguish between MHC class I-negative and -positive target cells may be explained by increased expression of Ly49 receptors, as described previously. However, the mechanisms for enhanced inhibition by MHC class I molecules appear to be unrelated to self tolerance in beta2m- mice, which may instead operate through mechanisms involving triggering pathways.

Animals↗
PubMed2000

Self-tolerance to the murine homologue of a tyrosinase-derived melanoma antigen: implications for tumor immunotherapy.

The human tyrosinase-derived peptide YMDGTMSQV is presented on the surface of human histocompatibility leukocyte antigen (HLA)-A*0201(+) melanomas and has been suggested to be a tumor antigen despite the fact that tyrosinase is also expressed in melanocytes. To gain information about immunoreactivity and self-tolerance to this antigen, we established a model using the murine tyrosinase-derived homologue of this peptide FMDGTMSQV, together with transgenic mice expressing the HLA-A*0201 recombinant molecule AAD. The murine peptide was processed and presented by AAD similarly to its human counterpart. After immunization with recombinant vaccinia virus encoding murine tyrosinase, we detected a robust AAD-restricted cytotoxic T lymphocyte (CTL) response to FMDGTMSQV in AAD transgenic mice in which the entire tyrosinase gene had been deleted by a radiation-induced mutation. A residual response was observed in the AAD(+)tyrosinase(+) mice after activation under certain conditions. At least some of these residual CTLs in AAD(+)tyrosinase(+) mice were of high avidity and induced vitiligo upon adoptive transfer into AAD(+)tyrosinase(+) hosts. Collectively, these data suggest that FMDGTMSQV is naturally processed and presented in vivo, and that this presentation leads to substantial but incomplete self-tolerance. The relevance of this model to an understanding of the human immune response to tyrosinase is discussed.

Amino Acid Sequence↗
PubMed1990

Self-tolerance to transgenic gamma delta T cells by intrathymic inactivation.

During their intrathymic differentiation, T lymphocytes expressing alpha beta T-cell receptors (TCR) are negatively and positively selected. This selection contributes to the establishment of self-tolerance and ensures that mature CD4+ and CD8+ cell populations are restricted by the self major histocompatibility complex. Little is known, however, about gamma delta T-cell development. To investigate whether selection operates in the establishment of the gamma delta T-cell class, we have generated transgenic mice using gamma- and delta-transgenes encoding a TCR that is specific for a product of a gene in the TL-region of the TLb haplotype. Similar numbers of thymocytes expressing the transgenic TCR were generated in mice of TLb and TLd haplotypes. But gamma delta thymocytes from TLb and TLd transgenic mice differed in cell size, TCR density and in their capacity to respond to TLb stimulator cells or interleukin-2 (IL-2). In contrast to gamma delta T cells from TLd transgenic mice, gamma delta T cells from TLb transgenic mice did not produce IL-2 and did not proliferate in response to TLb stimulator cells, but they did proliferate in the presence of exogenous IL-2. These results indicate that functional inactivation of self-antigen-specific T cells could contribute to the establishment of self-tolerance to thymic determinants.

Animals↗