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Results for “thymic selection”

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PubMed1994

Thymic development in human CD4 transgenic mice. Positive selection occurs after commitment to the CD8 lineage.

Developing T cells are positively selected on the basis of their recognition of polymorphic MHCs (major histocompatibility molecules). The CD4 and CD8 co-receptors, together with a compatible TCR-alpha beta, bind class II and class I MHC, respectively, delivering a signal that allows T cell maturation to proceed along the appropriate co-receptor lineage. During development, thymocytes first co-express CD4 and CD8 and subsequently commit to a single co-receptor phenotype. Debate exists over the stage at which positive selection occurs. Positive selection may precede or accompany co-receptor lineage commitment or occur subsequent to the acquisition of a single co-receptor phenotype. We developed transgenic (TG) mice expressing human CD4 (huCD4) on T cells. To study differentiation of CD8+ cells, huCD4 TG mice were bred with mice lacking class I MHC (class I-). This enabled us to assess maturation of mCD8+mCD4+huCD4+ thymocytes to mCD8+mCD4-huCD4+ cells after interaction between huCD4 and mclass II MHC. In the absence of huCD4, class I- mice failed to produce mCD8+ cells. However, expression of huCD4 allowed development of mCD8+mCD4-huCD4+ T cells, suggesting that selection of cells precommitted to the mCD8+mCD4- lineage occurred. Importantly, CD8+ T cells were increased in both the thymus and the periphery of huCD4 TG x class I- animals, indicating their intrathymic origin. V beta 14+ CD8+ T cells were also increased, as predicted for positive selection of CD8+ cells bearing class II-reactive TCRs. These data provide evidence that positive selection occurs at a late stage of thymocyte differentiation, after commitment to the CD8 lineage.

Animals↗
PubMed2003

Mutually antagonistic signals regulate selection of the T cell repertoire.

The sensitivity of T cells to agonist-induced death during development contrasts with their proliferative responses after agonist challenge in the periphery. The means by which TCR engagement results in these distinct outcomes is incompletely understood. It has been previously hypothesized that glucocorticoids (GC) modulate the threshold for thymocyte activation by blunting the consequences of TCR engagement. In support of this possibility, inhibition of GC production in fetal thymic organ culture was shown to result in CD4(+)CD8(+) thymocyte apoptosis. This was dependent upon MHC diversity, implying that endogenous GC might regulate antigen-specific selection. Similarly, mice expressing reduced GC receptor (GR) levels due to the presence of an antisense transgene have fewer CD4(+)CD8(+) thymocytes, which was due to an impaired transition from CD4(-)CD8(-) precursors and increased apoptosis. Here we ask how manipulating peptide diversity in the context of reduced GC signaling might affect T cell development and function. In mice with impaired GR expression there was a rescue of thymocyte cellularity and proportions as the diversity of peptides presented by self-MHC was reduced. Furthermore, whereas more CD4(+) T cells survived the selection process in mice expressing single-peptide-MHC class II complexes and reduced GR levels, these cells largely failed to recognize the same MHC molecules bound with foreign peptides. Together, these results support a role for endogenous GC in balancing TCR-mediated signals during thymic selection.

Animals↗
PubMed2000

Video-assisted mediastinoscopic resection of a thymic cyst by sternum lifting.

We performed mediastinoscopic surgery on two patients with a thymic cyst using a new instrument by sternum-lifting with tape. The merits of this technique are that a resection of the thymus and cyst can be achieved without a midline sternotomy, and under bilateral ventilation, and in cases with pleural adhesion. This technique can be applicable to most benign thymic lesions including thymectomy for myasthenia gravis and to selected cases with a malignant thymic tumor.

Aged↗
PubMed1993

T lymphocytes from human chimeras do recognize antigen in the context of allogeneic determinants of the major histocompatibility complex.

Human stem cells from the fetal liver can be transplanted to immunodeficient patients and reconstitute their immunity by giving rise to immunocompetent T lymphocytes of donor origin. Despite full HLA mismatch between donor and host, the helper T cells and the cytotoxic T cells which develop in these chimeric patients are totally functional. They recognize the antigenic peptides presented in the context of the foreign HLA molecules of the recipient, indicating that donor stem cells have been positively selected in the host environment, probably the thymic epithelial cells. By contrast, negative selection appears to be imposed upon T cells by donor hemopoietic cells, probably macrophages or dendritic cells, migrating from the transplant to the host thymus. Clonal deletion is then responsible for tolerance to donor HLA antigens, while clonal anergy explains tolerance to host HLA antigens.

Antigen-Presenting Cells↗
PubMed2004

Neurohypophysial receptor gene expression by thymic T cell subsets and thymic T cell lymphoma cell lines.

Neurohypophysial oxytocin (OT) and vasopressin (VP) genes are transcribed in thymic epithelium, while immature T lymphocytes express functional neurohypophysial receptors. Neurohypophysial receptors belong to the G protein-linked seven-transmembrane receptor superfamily and are encoded by four distinct genes, OTR, V1R, V2R and V3R. The objective of this study was to identify the nature of neurohypophysial receptor in thymic T cell subsets purified by immunomagnetic selection, as well as in murine thymic lymphoma cell lines RL12-NP and BW5147. OTR is transcribed in all thymic T cell subsets and T cell lines, while V3R transcription is restricted to CD4+CD8+ and CD8+ thymic cells. Neither V1R nor V2R transcripts are detected in any kind of T cells. The OTR protein was identified by immunocytochemistry on thymocytes freshly isolated from C57BL/6 mice. In murine fetal thymic organ cultures, a specific OTR antagonist does not modify the percentage of T cell subsets, but increases late T cell apoptosis further evidencing the involvement of OT/OTR signaling in the control of T cell proliferation and survival. According to these data, OTR and V3R are differentially expressed during T cell ontogeny. Moreover, the restriction of OTR transcription to T cell lines derived from thymic lymphomas may be important in the context of T cell leukemia pathogenesis and treatment.

Animals↗
PubMed2006

Developmental alterations in thymocyte sensitivity are actively regulated by MHC class II expression in the thymic medulla.

Developing thymocytes are positively selected if they respond to self-MHC-peptide complexes, yet mature T cells are not activated by those same self-complexes. To avoid autoimmunity, positive selection must be followed by a period of maturation when the cellular response to TCR signals is altered. The mechanisms that mediate this postselection developmental tuning remain largely unknown. Specifically, it is unknown whether developmental tuning is a preprogrammed outcome of positive selection or if it is sensitive to ongoing interactions between the thymocyte and the thymic stroma. We probed the requirement for MHC class II-TCR interactions in postselection maturation by studying single positive (SP) CD4 thymocytes from K14/A(beta)(b) mice, in which CD4 T cells cannot interact with MHC class II in the thymic medulla. We report here that SP CD4 thymocytes must receive MHC class II signals to avoid hyperactive responses to TCR signals. This hyperactivity correlates with decreased expression of CD5; however, developmental tuning can occur independently of CD5, correlating instead with differences in the distribution of Lck. Thus, the maturation of postselection SP CD4 thymocytes is an active process mediated by ongoing interactions between the T cell and MHC class II molecules. This represents a novel mechanism by which the thymic medulla prevents autoreactivity.

Animals↗
PubMed1994

How are alpha beta T cells positively selected in the thymus?

Thymus-derived (T) lymphocytes have the potential to express antigen receptors (TCR) that can recognize both self, as well as foreign antigens as they appear on the cell surface. In the thymus, positive selective allows the maturation of T cells that are able to see foreign antigens in conjunction with molecules encoded by genes of the major histocompatibility complex (MHC), whereas negative selection deletes auto-aggressive T cells. Control of T cell development is the only known function of the thymus. Therefore, it has been argued that recognition events responsible for selection of the T cell repertoire are guided by unique cellular interactions in the thymus. Here, we will show that positive selection can also occur on non-thymic cells. We will also argue that positive selection is not dependent on unique thymic accessory cells (AC) function. In other words, restricted recognition is not taught rather thymocytes learn it by themselves.

Animals↗
PubMed2003

The transcriptional repressor Gfi1 affects development of early, uncommitted c-Kit+ T cell progenitors and CD4/CD8 lineage decision in the thymus.

In the thymus, several steps of proliferative expansion and selection coordinate the maturation of precursors into antigen-specific T cells. Here we identify the transcriptional repressor Gfi1 as an important regulator of this maturation process. Mice lacking Gfi1 show reduced thymic cellularity due to an increased cell death rate, lack of proliferation, and a differentiation block in the very early uncommitted CD4-/CD8-/c-Kit+ cytokine-dependent T cell progenitors that have not yet initiated VDJ recombination. In addition, Gfi1-deficient mice show increased major histocompatibility complex class I-restricted positive selection and develop significantly more CD8+ cells suggesting a requirement of Gfi1 for a correct CD4/CD8 lineage decision. Absence of Gfi1 correlates with high level expression of the genes for lung Krüppel-like factor (LKLF), inhibitor of DNA binding (Id)1 and Id2, suggesting the existence of new regulatory pathways in pre-T cell development and thymic selection in which Gfi1 acts upstream of LKLF as well as the E-proteins, which are negatively regulated by Id1 and Id2.

Animals↗
PubMed1993

Positive selection of CD8+ T cells induced by major histocompatibility complex binding peptides in fetal thymic organ culture.

We have used an in vitro system to study the effects of major histocompatibility complex class I binding peptides on thymic development. Fetal thymus lobes from mice deficient in the class I light chain (beta 2 microglobulin or beta 2 M-/-) were cultured for 10 d in vitro, during which time T cell precursors develop into mature T cells. In these organ cultures, as in the adult or neonatal beta 2 M-/- thymus, CD8+ mature T cells did not develop, demonstrating that the mature T cells seen during early murine thymic development are the result of the positive selection process. To these cultures we added various class I binding peptides with or without a source of exogenous beta 2M. CD8+ T cells developed to various degrees only in the presence of beta 2M and peptides. Using peptide mixtures of differing complexity, we showed that the efficiency of this process is dependent more on peptide complexity than on peptide concentration. These data argue for a specific role for peptides in the process of positive selection. Furthermore, this culture system should be useful in identifying peptides that can promote positive selection of cells expressing a specific T cell receptor (TCR) in TCR transgenic mice.

Amino Acid Sequence↗
PubMed1993

Bacterial superantigens mediate T cell deletions in the mouse severe combined immunodeficiency-human liver/thymus model.

The ability to analyze T cell receptor (TCR) thymic repertoire shaping in humans by self and foreign ligands is hampered by the lack of suitable models. We recently documented that the mouse severe combined immunodeficiency (SCID)-human fetal liver/thymus model recapitulates the TCR V beta gene repertoire of human thymocytes. Here, we show that an exogenous superantigen, staphylococcal enterotoxin B, administered to such mice induces clonal deletions in both CD4+8- and CD8+4- cells involving the same human V beta clones that are selected in vitro by this toxin. This model, therefore, may allow comprehensive studies into the effects of microbial and other agents on human T cell thymic selection processes in a biologically relevant setting.

Animals↗
PubMed1997

Oligoclonal peripheral T-cell lymphocytosis as a result of aberrant T-cell development in a cortical thymoma.

A 42-year-old man presented with a locally invasive cortical thymoma. Before chemotherapy was commenced 36 months after presentation, an unusual peripheral lymphocytosis of 19 x 10(9)/l had slowly developed over time. After the first course of chemotherapy, the lymphocytosis showed a sharp decline to normal absolute cell numbers and subsequently remained at normal levels. Currently, the patient is in stable partial remission and doing well. Immunophenotypic analysis showed a mature T-cell phenotype with 78% TcR-a beta and 16% TcR-gamma delta in the absence of an immature component. Pretreatment Southern blot analysis of peripheral blood mononuclear cells showed an oligoclonal pattern with 13-20 rearranged fragments of different intensity for the TcR beta-gene. TcR gamma also showed a pattern compatible with an oligoclonal proliferation. After treatment, after normalization of absolute blood counts, the distribution of T-cell subsets still showed a slightly aberrant pattern. Immunophenotypic analysis of a blood sample taken 6 months later, also at normal absolute cell counts, showed an increase of thymocytes as well as of mature T cells with a polyclonal pattern on Southern blot analysis. These findings may be interpreted as the result of aberrant positive and negative selection and development of thymocytes in the microenvironment of neoplastic thymic epithelial cells and clonal selection through continuous peripheral stimulation. Moreover, this case stresses the importance of integrated interpretation of clinical, morphological, immunophenotypical, and molecular data to gain insight in unusual clinical problems.

Adult↗
PubMed2006

Effects of estrogen receptor subtype-selective agonists on immune functions in ovariectomized mice.

Estrogens have multiple influences on immune functions. Estrogen receptors (ERs) have two distinct subtypes - alpha and beta. To explore the specific roles of each ER subtype in estrogen-mediated immunomodulation, we investigated the effects of ER subtype-selective agonists on immune functions in ovariectomized Balb/c mice. Treatment with ERalpha-selective agonist propyl pyrazole triol (PPT) caused thymic atrophy and significant changes in thymic CD4/CD8 phenotypic profile. In contrast, ERbeta-selective agonist diarylpropionitrile (DPN) alone had no effect on thymic weight, cellularity or CD4/CD8 phenotype expression. When coadministered with PPT, DPN partially antagonized PPT-evoked decrease in thymic cellularity and also partially attenuated PPT-induced shifts in thymic T-cell phenotype. These results indicate that ERalpha plays a predominant role in estrogen-induced thymic atrophy and ERbeta activation may partially down-regulate ERalpha-mediated effects on thymic cellularity and T-cell phenotype expression. In addition, PPT administration induced a reduction in the percentage of mature B cells in the spleen, and enhanced IFN-gamma production but suppressed IL-6 production from in vitro Con A-stimulated splenocytes as estradiol (E(2)) did, whereas DPN treatment had no effects either alone or with PPT, suggesting ERalpha mediates these estrogen actions. Treatment with PPT or DPN did not augment anti-DNP antibody production after DNP-KLH immunization as E(2) did, implying that not merely one ER signaling pathway is involved in mediating estrogen's effects on specific humoral immune responses. Our study further indicates ER subtype-selective agonists provide a novel approach to explore each ER subtype-mediated immunomodulation.

Animals↗
PubMed1996

Characterization of the AKR thymic microenvironment and its influence on thymocyte differentiation and lymphoma development.

The thymic stroma has long been implicated in AKR thymic leukaemia. In this study an extensive panel of monoclonal antibodies was used to investigate changes in the AKR thymic microenvironment, in parallel with thymocyte differentiation of normal (2 month), preleukaemic (5-7 month) and leukaemic (> 7 month) mice. We found select alterations in the thymic stroma, including a loss of isolated medullary antigens and changes in MTS 32, a mAb detecting an antigen on both thymocytes and stroma in the thymic cortex. Stromal alterations were accompanied by shifts in thymocyte differentiation and the appearance of the leukaemogenic mink cell focus-forming (MCF) murine leukaemia virus.

Analysis of Variance↗
PubMed2003

The chemokine receptor CCR8 mediates rescue from dexamethasone-induced apoptosis via an ERK-dependent pathway.

Several chemokines have been shown to regulate cellular apoptosis following discrete stimuli. It was previously demonstrated that the CC chemokine CCL1 (I-309) rescues thymic lymphoma cells from apoptosis by unknown mechanisms. The aim of our study was to characterize the role of the CC chemokine receptor 8 (CCR8), the only described receptor for CCL1, in the rescue of murine thymic lymphoma cells and murine thymocytes from dexamethasone (dex)-induced apoptosis. We show here that the CCR8-restricted agonist Kaposi sarcoma-associated herpesvirus-encoded chemokine viral macrophage-inflammatory protein-1 (vMIP-1) rescues thymic lymphoma cells from dex-induced apoptosis, similar to CCL1, and that such rescue is extracellular-regulated kinase-dependent. Although it has been hypothesized that the rescuing effect of CCL1 from apoptosis could be CCR8-mediated, here, we formally demonstrate the role of such receptor as its selective antagonist encoded by the MC148 gene of molluscum contagiosum virus MC148/vMCC-I inhibits v-MIP-1- and CCL1-induced rescue activity. In addition, CCR8 ligands inhibit dex-induced apoptosis of murine thymocytes with potential implications for thymic selection.

Animals↗
PubMed2001

Thymic T-cell tolerance of neuroendocrine functions: physiology and pathophysiology.

Intimate interactions between the two major systems of cell-to-cell communication, the neuroendocrine and immune systems, play a pivotal role in homeostasis and developmental biology. During phylogeny as well as during ontogeny, the molecular foundations of the neuroendocrine system emerge before the generation of diversity within the system of immune defenses. Before reacting against non-self infectious agents, the immune system has to be educated in order to tolerate the host molecular structure (self). The induction of self-tolerance is a multistep process that begins in the thymus during fetal ontogeny (central tolerance) and also involves anergizing mechanisms outside the thymus (peripheral tolerance). The thymus is the primary lymphoid organ implicated in the development of competent and self-tolerant T-cells. During ontogeny, T-cell progenitors originating from hemopoietic tissues (yolk sac, fetal liver, then bone marrow) enter the thymus and undergo a program of proliferation, T-cell receptor (TCR) gene rearrangement, maturation and selection. Intrathymic T-cell maturation proceeds through discrete stages that can be traced by analysis of their cluster differentiation (CD) surface antigens. It is well established that close interactions between thymocytes (pre-T-cells) and the thymic cellular environment are crucial both for T-cell development and for induction of central self-tolerance. Particular interest has focused on the ability of thymic stromal cells to synthesize polypeptides belonging to various neuroendocrine families. The thymic repertoire of neuroendocrine-related precursors recapitulates at the molecular level the dual role of the thymus in T-cell negative and positive selection. Thymic precursors not only constitute a source of growth factors for cryptocrine signaling between thymic stromal cells and pre-T-cells, but are also processed in a way that leads to the presentation of self-antigens by (or in association with) thymic major histocompatibility complex (MHC) proteins. Thymic neuroendocrine self-antigens usually correspond to peptide sequences highly conserved during the evolution of their corresponding family. The thymic presentation of some neuroendocrine self-antigens does not seem to be restricted by MHC alleles. Through the presentation of neuroendocrine self-antigens by thymic MHC proteins, the T-cell system might be educated to tolerate main hormone families. More and more recent experiments support the concept that a defect in thymic tolerogenic function is implicated as an important factor in the pathophysiology of autoimmunity.

Animals↗
PubMed1993

Thymus epithelium induces tissue-specific tolerance.

Most current models of T cell development include a positive selection step in the thymus that occurs when T cells interact with thymic epithelium and a negative selection step after encounters with bone marrow-derived cells. We show here that developing T cells are tolerized when they recognize antigens expressed by thymic epithelium, that the tolerance is tissue specific, and that it can occur by deletion of the reactive T cells.

Animals↗
PubMed1990

Selective elimination of double-positive immature thymocytes by a thymic epithelial cell line.

A cloned epithelial cell line, TEL-2, has been established from the stroma tissues of normal mouse thymus. Incubation of mouse thymocytes on TEL-2 cells resulted in the selective elimination of double-positive (CD4+CD8+) cells from the culture, whereas single-positive (CD4+CD8- or CD4-CD8+) thymocytes remaining in the culture were concentrated in non-integrated cell population. The CD3- or CD3 low-positive thymocytes were also eliminated by the TEL-2 cells from the culture, followed by the concentration of CD3 high-positive cells in the culture. Only intact viable thymocytes were integrated into TEL-2 cells. Electron microscopic examination showed that the integrated cells into TEL-2 cytoplasm were gradually degenerated. Mature single-positive T cells, mature B cells or double-negative thymocytes were not integrated into TEL-2 cells. The TEL-2 cell may provide information on the mechanism of selective disappearance of double-positive immature cells from the thymus.

Animals↗