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Results for “thymic selection”

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PubMed1998

Involvement of c-myc in the resistance of non-obese diabetic mice to glucocorticoid-induced apoptosis.

Non-obese diabetic (NOD) mice spontaneously develop insulin-dependent diabetes mellitus (IDDM) as a consequence of autoimmune aggression of beta cells of the endocrine pancreas by T cells. T lymphocytes of NOD mice are resistant to apoptosis induced by glucocorticoids, or by starving or DNA-damaging treatments, a feature that was interpreted as being linked to escape of autoreactive T cells from thymic negative selection. c-myc is one of the gene targets of glucocorticoids (GC), its expression being down-regulated by the activated GC-GC receptor complex. We investigated here whether expression of Myc protein, in response to dexamethasone stimulation, was the same in NOD mice and in non-autoimmune strains, namely NON, BALB/c and C57Bl.6. We found a consistent increase in the levels of Myc protein after GC-treatment of lymphocytes of NOD mice, a finding that was in contrast to the down-regulation of c-myc that we observed in lymphocytes from mice not prone to diabetes. We also report that, rather than a absolute resistance to GC-induced cell death, NOD mice display a delayed apoptotic response to GC. We propose that the resistance of NOD mice lymphocytes to GC-induced apoptosis is because of inhibition of the repressive action of GC-GR complexes at the level of c-myc transcription. This deficient action of GC-GR results in increased production of nuclear Myc protein, peculiar to NOD mice cells, following their treatment with GC.

Animals↗
PubMed1999

Minute defects in the expression of MHC E molecules lead to impaired protection from autoimmunity in NOD mice.

The E complex of the major histocompatibility complex (MHC) can prevent the spontaneous development of diabetes in nonobese diabetic (NOD) mice transgenic for the Ea gene. None of three promoter-mutated Ea constructs with Ea expression directed to different subsets of immunocompetent cells exerts full protection in NOD mice. The promoter-mutated constructs are all capable of mediating intrathymic elimination of I-E-restricted T cells. Thus, thymic negative selection is not responsible for the protective effect but a more complex effect is likely. Here we show that combinations of two or three different mutated Ea constructs do not protect against intra-islet insulitis either. We also show that spleen cells from protected animals are sufficient to protect NOD mice in adoptive transfer experiments. The only detectable expression defects in splenic cells or cells influencing the repertoire of splenic cells are in the B-cell compartment. Furthermore, in three construct combinations, the differences to wild-type expression are extremely small. Thus, we conclude that even minute disturbances of the E expression pattern might reduce the protection of NOD mice from insulitis.

Adoptive Transfer↗
PubMed2001

The thymus of the hairless rhino-j (hr/rh-j) mice.

The hairless (hr) gene is expressed in a large number of tissues, primarily the skin, and a mutation in the hr gene is responsible for the typical cutaneous phenotype of hairless mice. Mutant hr mouse strains show immune defects involving especially T cells and macrophages, as well as an age-related immunodeficiency and an accelerated atrophy of the thymus. These data suggest that the hr mutation causes a defect of this organ, although hr transcripts have not been detected in fetal or adult mice thymus. The present study analyses the thymus of young (3 mo) and adult (9 mo) homozygous hr-rh-j mice (a strain of hairless mice) by means of structural techniques and immunohistochemistry to selectively identify thymic epithelial cells, dendritic cells, and macrophages. There were structural alterations in the thymus of both young and adult rh-rh-j mice, which were more severe in older animals. These alterations consisted of relative cortical atrophy, enlargement of blood vessels, proliferation of perivascular connective tissue, and the appearance of cysts. hr-rh-j mice also showed a decrease in the number of epithelial and dendritic cells, and macrophages. Taken together, present results strongly suggest degeneration and accelerated age-dependent regression of the thymus in hr-rh-j mice, which could explain at least in part the immune defects reported in hairless mouse strains.

Aging↗
PubMed2003

Regulatory CD8+ T cells fine-tune the myelin basic protein-reactive T cell receptor V beta repertoire during experimental autoimmune encephalomyelitis.

A significant number of self-reactive T cell clones escape thymic negative selection and are released into the periphery, where some are potentially pathogenic. The clonal expansion of self-reactive T cells is known to be limited during initial antigen encounter by apoptotic or anergic mechanisms, regulatory CD4+ T cells, and cytokines. Here we report that superimposed on these mechanisms, during the evolution of autoimmunity in experimental autoimmune encephalomyelitis (EAE), CD8+ T cells are induced, which fine-tune the peripheral self-reactive T cell receptor (TCR) repertoire. We assayed the myelin basic protein-reactive TCR repertoire in naive, EAE-recovered mice as well as EAE-recovered mice depleted of CD8+ T cells by TCRV beta surface expression, complementarity-determining region 3 length distribution, and complementarity-determining region 3 sequencing analysis. In EAE-recovered mice, certain myelin basic protein-reactive CD4+V beta 8.2+ clones are significantly decreased and this decrease is not observed if CD8+ T cells were depleted from these mice. The clones that persist in CD8+ T cell-intact mice are highly diverse in contrast to the clones expanded in CD8+ T cell-depleted mice, which are dominated by the significant outgrowth of a few clones. Importantly, the T cell clones that expand in the absence of CD8+ T cell control are enriched in potentially pathogenic self-reactive T cell clones capable of inducing EAE in vivo.

Adoptive Transfer↗
PubMed1995

Positive selection of mouse NK1+ T cells by CD1-expressing cortical thymocytes.

Mouse NK1+ T cells constitute a subset of alpha/beta TCR+ T cells that specialize in the rapid production of cytokines, in particular IL-4, and may promote the differentiation of Th2-type CD4 T cells. Their TCRs, like those of a homologous subset of human T cells, use an invariant TCR alpha chain and were recently shown to be specific for the beta 2-microglobulin-associated, MHC class I-like CD1 molecules, which are encoded outside the MHC. In contrast to mainstream thymocytes, which recognize their positively selecting MHC ligand on thymic epithelial cells, positive selection of NK1+ T cells requires their CD1 ligand to be expressed on bone marrow-derived cells. To investigate the nature of the bone marrow-derived cell involved, chimeric mice were constructed with tissues from normal, SCID, and MHC-deficient mice, so that CD1 could be selectively expressed by different subsets of bone marrow-derived cells in the thymus. CD1 expression was also directly assessed using an anti-CD1 mAb, and a CD1-specific T cell hybridoma. The results suggest that immature (CD4+8+ double-positive) cortical thymocytes are the source of CD1 presentation for positive selection of NK1+ T cells.

Animals↗
PubMed2004

Inactivation of c-Cbl reverses neonatal lethality and T cell developmental arrest of SLP-76-deficient mice.

c-Cbl is an adaptor protein that negatively regulates signal transduction events involved in thymic-positive selection. To further characterize the function of c-Cbl in T cell development, we analyzed the effect of c-Cbl inactivation in mice deficient in the scaffolding molecule SLP-76. SLP-76-deficient mice show a high frequency of neonatal lethality; and in surviving mice, T cell development is blocked at the DN3 stage. Inactivation of c-cbl completely reversed the neonatal lethality seen in SLP-76-deficient mice and partially reversed the T cell development arrest in these mice. SLP-76(-/-) Cbl(-/-) mice exhibited marked expansion of polarized T helper type (Th)1 and Th2 cell peripheral CD4(+) T cells, lymphoid infiltrates of parenchymal organs, and premature death. This rescue of T cell development is T cell receptor dependent because it does not occur in recombination activating gene 2(-/-) SLP-76(-/-) Cbl(-/-) triple knockout mice. Analysis of the signal transduction properties of SLP-76(-/-) Cbl(-/-) T cells reveals a novel SLP-76- and linker for activation of T cells-independent pathway of extracellular signal-regulated kinase activation, which is normally down-regulated by c-Cbl.

Adaptor Proteins, Signal Transducing↗
PubMed1996

CD45 up-regulation during lymphocyte maturation.

CD4+ CD8+ double-positive thymocytes differentiate into CD4+ and CD8+ single-positive T cells during thymic positive selection. This process requires the interaction between the TCR and self MHC molecules. In this context we have analyzed the expression of CD45, an abundant transmembrane protein tyrosine phosphatase, and describe here its differential surface expression during T cell maturation. Using four-color FACS analysis of thymocytes from normal as well as TCR-transgenic mice we demonstrate that CD45 is up-regulated only during positive selection concomitantly with the TCR-CD3 complex and the transient early activation marker CD69, but that this up-regulation precedes heat stable antigen down-regulation. The tight linkage of the up-regulation of the TCR-CD3 complex and CD45 may be required because the CD45 tyrosine phosphatase plays a role in modulating signal transduction by the TCR-CD3 complex during positive selection. In addition, our findings argue for a regulation mechanism that adapts the CD45 levels to increasing antigen receptor levels on mature T cells and B cells.

Animals↗
PubMed2002

Development of CD25(+) T cells secreting transforming growth factor-beta1 by altered peptide ligands expressed as self-antigens.

This study demonstrates that CD4(+) T cells specific for an altered self-antigen differentiate to T cells secreting transforming growth factor (TGF)-beta1. In this study, we utilized mice expressing an altered peptide ligand containing a single amino acid substitution of moth cytochrome c 88-103 peptide. In these mice, antigen-specific T cells escaping thymic negative selection differentiated into T cells with an effector/memory phenotype, CD44(high), CD45RB(low), CD62L(-) and CD25(intermediate). The expression of CD25 and high levels of CD44 was initiated in the thymus during the development from CD4(+)CD8(+) to CD4(+); a large proportion of maturing CD4(+) thymocytes expressed both CD25 and high levels of CD44. Upon antigen stimulation, CD4(+) T cells derived from these mice did not proliferate or secrete IL-2, but secreted TGF-beta1. Neutralizing antibodies to TGF-beta1 reversed the impaired proliferative responses to the antigen, suggesting that TGF-beta1 secreted from these T cells negatively regulates T cell responses.

Amino Acid Sequence↗
PubMed2002

Factors influencing the patterns of T lymphocyte allorecognition.

BACKGROUND: Strong alloreactive T cell responses are a menace in transplantation surgery and their menagement requires understanding the basis of alloreactivity. Alloantigen recognition can be peptide independent, peptide specific, or peptide dependent. The mechanisms influencing each recognition pattern are largely unknown. METHODS: Peptide dependence was examined in vitro by adding peptides to antigen processing-deficient cell line used as target in cytotoxic T cell assays. Responses to major histocompatibility complex (MHC) alleles most homologous to self were recently shown to be more peptide dependent than to those with lesser homology to self. Hence, peptide reactivity in vivo was estimated based on relative strengths of alloreactive responses to more homologous and less homologous MHC alleles. RESULTS: Alloreactive CD8+ TCR repertoire in beta2-microglobulin-deficient mice is preferentially peptide independent. The peptide-specific component is acquired as a function of wild-type thymic epithelium grafting. Irrespective of the presence of the peptide-specific component, in vivo alloantigenic priming was associated with a greater sensitivity to the MHC structure than was in vitro priming. CONCLUSIONS: Thymic positive selection and the mode of alloreactivity induction are the major independent factors determining the patterns of alloantigen recognition.

Animals↗
PubMed1997

Mechanisms of peripheral T-cell tolerance.

It is becoming increasingly clear that the control of self-reactivity involves peripheral mechanisms that supplement thymic negative selection. It is now generally accepted that T-cell activation depends upon both T-cell receptor engagement and the delivery of B7-mediated costimulation by specialized antigen presenting cells (APC). In contrast, failure to deliver B7-mediated costimulation can result in the induction of antigen-specific non-responsiveness. In physiological terms, costimulation-deficient antigen presentation is the prerogative of those cells that do not express B7 molecules, even during inflammatory conditions, such as tissue parenchymal cells. The consequences of such costimulation-deficient antigen presentation are illustrated by the allospecific tolerance that is observed in animal models of transplantation following the depletion of bone marrow-derived APC from an allograft. In this paper the possible role of antigen presentation by tissue parenchymal cells in the induction and maintenance of peripheral tolerance is discussed, with particular attention to the important contribution that the liver may make to these events.

Antigen Presentation↗
PubMed1996

Using transgenic mouse models to dissect the pathogenesis of virus-induced autoimmune disorders of the islets of Langerhans and the central nervous system.

Viruses have often been associated with autoimmune diseases. One mechanism by which self-destruction can be triggered is molecular mimicry. Many examples of cross-reactive immune responses between pathogens and self-antigens have been described. This review presents two transgenic models of autoimmune disease induced by a virus through activation of anti-self lymphocytes. Viral antigens are expressed as transgenes either in beta-cells of the pancreas or in the oligodendrocytes of the CNS. Infection by a virus encoding the same gene activated autoreactive T cells that cleared the viral infection, and as a consequence of transgene expression resulted in organ-specific autoimmune disease. In both transgenic mouse models, autoreactive lymphocytes that escaped thymic negative selection were present in the periphery. Several factors are described that play a role in the regulation of the self-reactive process precipitated by a viral infection. These include the quantity of activated autoreactive T cells, the affinity of these T cells, the number of memory T cells generated following primary infection, costimulation by accessory molecules, and the types and locations of cytokines produced. In addition, unique barriers exist in target tissues that prevent or suppress autoreactive responses and define to a large extent the outcome of disease. Restimulation of autoreactive memory lymphocytes may be required to bypass these barriers and enhance autoimmune disease. Therapy directed at modifying these factors can reduce and even prevent autoimmune disease after it has been initiated.

Animals↗
PubMed1997

T cell repertoire: genomic or somatic bias toward recognition of major histocompatibility complex molecules?

The prevailing concept about a major influence of thymic positive selection on shaping the T cell repertoire during ontogeny is confronted with an old idea emphasizing a dominant role for genetic (evolutionary) factors in molding the recognition potential of mature T cells. Our recent results are not readily interpreted without introducing a new version of the old concept, according to which complementarity to the major histocompatibility complex peptide-binding site is a major evolutionary selective pressure on T cell antigen receptor variable genes, with alloreactivity being a reflection of this fact.

Animals↗
PubMed1993

Tolerance and ways to break it.

The overall picture as regards cellular mechanisms in immunologic tolerance is thus clear. Thymic negative selection is an important and dominant mechanism for both CD4+ and CD8+ T cells for those antigens (and they may be very many indeed), the peptides of which get expressed within the thymus. The induction of anergy among peripheral T lymphocytes may represent an ancillary mechanism in some cases, but this is not as clear as it appeared 2 or 3 years ago. Evidently, in many cases, T cells simply ignore antigens present only within specialized organs, and these T cells, even if only of low affinity for the antigen in question, could be provoked into autoimmunity if sufficient help is provided, for example, through localized production of IL-2 or through provision of cross-reactive help. B-cell tolerance is also proven and involves deletional mechanisms (most likely maturation arrest) or functional inactivation (clonal anergy). The former phenomenon dominates for self-antigens that strongly cross-link the B cell's Ig receptors and the latter for weaker negative signals. Despite these two mechanisms, clonal ignorance prevails for many self-antigens. The secondary B-cell repertoire is also largely free of anti-self B cells, lack of T-cell help being a major factor in preventing the development of anti-self memory B cells. Therefore, to have the best chance of creating an immunogenic antitumor vaccine, a few simple and rather obvious rules must be followed. The antigen in question must be presented in such a way as to be palatable to "professional" antigen-presenting cells, particularly dendritic cells and macrophages. Immunotherapy protocols should avoid at all costs the widespread distribution of the antigen in question through the extracellular fluids. Indeed, it is possible that widespread circulation of a tumor-associated antigen through the serum and lymph because of large-scale shedding from the tumor cell may already have created a substantial degree of tolerance to the antigen in question in both T- and B-cell populations. If that has happened, it becomes particularly important to create a cancer vaccine capable of inducing help. This may well involve coupling of the most important epitopes to some highly immunogenic and foreign carrier. A wide choice of adjuvants is available for the designer of tumor vaccines, and in this regard the cancer immunotherapy community has much to learn from the rapidly developing field of infectious disease vaccinology using recombinant and other vaccines.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2005

Endogenous superantigens shape response to exogenous superantigens.

Endogenous superantigen-mediated thymic negative selection resulted in a paucity of mature T cells bearing T-cell receptor (TCR) Vbeta8 in the periphery. Consequently, the magnitude of immune response to exogenous superantigen staphylococcal enterotoxin B, which activates TCR Vbeta8(+) T cells, was significantly reduced and conferred protection from superantigen-induced mortality.

Animals↗
PubMed1990

The molecular basis of T-cell specificity.

Studies of TCR expression in antigen-specific immune responses have provided a large body of information correlating the primary structure of the TCR with specificity. Much has been learned regarding the mechanisms for the generation of TCR diversity and the selection of TCR V elements in immune responses. However, the exact nature of the trimolecular complex found during the TCR/antigen/MHC interaction awaits the structural characterization of the TCR by crystallography. Just as describing the three-dimensional structure of MHC molecules and defining their putative antigen-binding site have made it possible to interpret with fresh insight the wealth of functional data regarding antigen/MHC binding and alloreactivity, similar characterization of the TCR structure will allow more definitive interpretation of all the current data with respect to TCR usage in antigen-specific immune responses. It should also facilitate the study of the molecular basis of positive and negative TCR selection during thymic ontogeny. Finally, the identification of T-cell superantigens and their ability to stimulate T cells on the basis of TCR V beta expression alone has defined a new and distinct type of TCR/ligand interaction. The fact that bacterial products such as staphylococcal and streptococcal toxins as well as the mitogenic moiety produced by some mycoplasma are included within this class of antigens suggests that TCR recognition of superantigens may have major clinical significance. It is important to determine the structural basis of T-cell activation by these antigens.

Animals↗
PubMed2006

Early CD30 signaling is critical for adoptively transferred CD4+CD25+ regulatory T cells in prevention of acute graft-versus-host disease.

Murine CD4+CD25+ regulatory T cells (Treg cells) reduce acute graft-versus-host disease (aGvHD). However, surface molecules critical for suppression are unclear. Deficiency of CD30 (CD30-/-) leads to impaired thymic negative selection and augmented T-cell autoreactivity. Therefore, we investigated the role of CD30 signaling in Treg-cell function during aGvHD. Treg cells derived from CD30-/- animals were significantly less effective in preventing aGvHD lethality. Early blockade of the CD30/CD153 pathway with a neutralizing anti-CD153 mAb reduced Treg-mediated protection from proinflammatory cytokine accumulation and donor-type T-cell apoptosis. In vivo bioluminescence imaging demonstrated intact homing but reduced expansion of luciferase-expressing Treg cells when CD153 was blocked during the early phase after adoptive transfer. CD30 surface expression on Treg cells increased with alloantigen exposure, and CD153 expression on recipient-type dendritic cells increased in the presence of a proinflammatory environment. These data demonstrate that early CD30 signaling is critical for Treg-mediated aGvHD protection after major MHC-mismatch bone marrow transplantation.

Acute Disease↗
PubMed1998

Intraepithelial lymphocytes: origins, distribution, and function.

Intraepithelial lymphocytes (IEL) are associated with the intestinal tract, respiratory tract, genitourinary tract epithelium, and the skin and are the first immune system cells to encounter pathogens that have invaded an epithelial surface. IEL are predominantly T cells (CD3+) with CD8+ cells predominating at most, but not all, sites. Both TCR alphabeta+ and TCR gammadelta+ cells are found within IEL populations and an increasing body of evidence suggests that some IEL may arise extrathymically. The presence within intestinal IEL of cells expressing potentially self-reactive TCR suggests that T cell selection within epithelia may differ from thymic T cell selection although recent evidence suggests that these cells may in fact be nonresponsive. IEL exhibit various cytotoxic activities including alloreactive and virus-specific CTL activity, NK activity and spontaneous cytotoxicity, activities consistent with an immune surveillance or first line of defence role. IEL also appear activated in vivo and secrete a variety of cytokines. Subsets of IEL have been shown to provide B cell help, to play a role in the maintenance of oral tolerance and to regulate epithelial cell function. In this review the morphology, distribution and phenotype of IEL, the potential for extrathymic development and possible functions of this unique lymphoid population are discussed.

Cell Movement↗
PubMed2005

Mechanisms of CD8+ T cell peripheral tolerance to our own antigens.

CD8+ T cells represent a powerful arm of the adaptive immunity that is particularly effective against intracellular pathogens. These cells might also participate in the generation and sustenance of autoimmune responses. The escape of a certain number of CD8+ autoreactive T lymphocytes from thymic negative selection occurs normally in all individuals, but this event is rarely associated with the onset of autoimmune diseases. Several peripheral mechanisms have been evolved by the immune system to take control of these potentially harmful self-aggressive cytotoxic CD8+ T cells. In the present review, we will discuss the principal strategies by which the immune system is capable of maintaining CD8+ T cell tolerance to self, thus making them ineffective to harm their own host but still capable to defend the host against foreign invaders.

Animals↗