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PubMed1996

Mouse mammary tumor virus production by thymic epithelial cells in vivo.

Exogenous mouse mammary tumor viruses (MMTV) replicate in the mammary glands of infected females, and so infect the suckling pups. We have previously shown that the virus is rapidly disseminated to all the lymphoid organs, including the thymus. The present electron microscope immunohistochemical study describes the viral production site in the thymus. Viral buds and viral proteins were restricted to the thymus medullary epithelial cells. MMTV-encoded proteins were identified on the free viral particles and on the budding ones, the ribosomes, the membrane of the endoplasmic reticulum, and on the membrane of the medullary type II epithelial cell vacuolar network. The thymus medullary epithelial cells can thus integrate the virus and allow viral replication. The results support earlier results indicating that in some experimental conditions, epithelial cells may be involved in MMTV-induced negative selection by showing that thymic epithelial cells do express MMTV-encoded proteins.

Animals↗
PubMed2000

HLA transgenic mice as models of human autoimmune diseases.

MHC class II alleles have been linked to several human autoimmune diseases such as rheumatoid arthritis (RA), Type I diabetes, and multiple sclerosis (MS). Although the mechanisms by which expression of certain MHC class II molecules predispose an individual to a particular autoimmune disease are not known, it is clear that increased susceptibility is associated with the polymorphic regions unique to these predisposing HLA alleles. These polymorphic differences may influence susceptibility by selecting potential autoreactive T cells during thymic education. Alternatively, nonsusceptible alleles may either delete or fail to select these potential autoimmune T cells, thus reducing the possibility of developing disease. In the periphery, the unique specificity of the HLA molecule derived from a susceptible allele may then recognize and present an autoantigenic peptide or foreign peptide that may cross-react with an autoantigen, activating these autoreactive T cells and leading to disease. To dissect these possibilities and to determine the exact role of particular HLA-DR or DQ molecules in disease susceptibility, we have generated several lines of HLA-DR and DQ transgenic mice. In this review, we present data summarizing the functions of these HLA class II molecules using well-established mouse models for autoimmune diseases.

Animals↗
PubMed1996

Thymic and extrathymic T cell development.

The majority of T cells located in peripheral blood, spleen and lymph nodes are dependent on the thymus for proper differentiation and function. Only a minority of T lymphocytes located in these lymphoid organs is thymic-independent. In contrast, a large number of thymus-independent T cells is present in the gut epithelium. This review deals with phenotypic and functional characteristics of T cell development, summarizes the knowledge on the cytokine requirement in this process and describes positive and negative selection. The differences between thymic-dependent and thymic-independent T cells are emphasized, including selection processes, CD4-CD8 expression and the composition of the CD3 complex.

Animals↗
PubMed2006

TCRgammadelta+ large granular lymphocyte leukemias reflect the spectrum of normal antigen-selected TCRgammadelta+ T-cells.

T-cell large granular lymphocytes (LGL) proliferations range from reactive expansions of activated T cells to T-cell leukemias and show variable clinical presentation and disease course. The vast majority of T-LGL proliferations express TCRalphabeta. Much less is known about the characteristics and pathogenesis of TCRgammadelta+ cases. We evaluated 44 patients with clonal TCRgammadelta+ T-LGL proliferations with respect to clinical data, immunophenotype and TCR gene rearrangement pattern. TCRgammadelta+ T-LGL leukemia patients had similar clinical presentations as TCRalphabeta+ T-LGL leukemia patients. Their course was indolent and 61% of patients were symptomatic. The most common clinical manifestations were chronic cytopenias - neutropenia (48%), anemia (23%), thrombocytopenia (9%), pancytopenia (2%) - and to a lesser extent splenomegaly (18%). Also multiple associated autoimmune (34%) and hematological (14%) disorders were found. Leukemic LGLs were predominantly positive for CD2, CD5, CD7, CD8, and CD57, whereas variable expression was seen for CD16, CD56, CD11b, and CD11c. The Vgamma9/Vdelta2 immunophenotype was found in 48% of cases and 43% of cases was positive for Vdelta1, reflecting the TCR-spectrum of normal TCRgammadelta+ T-cells in adult PB. Identification of the well-defined post-thymic Vdelta2-Jdelta1 selection determinant in all evaluable Vgamma9+/Vdelta2+ patients, is suggestive of common (super)antigen involvement in the pathogenesis of these TCRgammadelta+ T-LGL leukemia patients.

Adult↗
PubMed1989

Positive selection of CD4+ T cells mediated by MHC class II-bearing stromal cell in the thymic cortex.

T lymphocytes differentiate in the thymus, where functionally immature, CD4+CD8+ (double positive) thymocytes develop into functionally mature CD4+ helper cells and CD8+ cytotoxic (single positive) T cells. The thymus is the site where self-reactive T cells are negatively selected (clonally deleted) and where T cells with the capacity to recognize foreign antigens in association with self-proteins encoded by the major histocompatibility complex (MHC) are positively selected. The net result of these developmental pathways is a T-cell repertoire that is both self-tolerant and self-restricted. One unresolved issue is the identity of the thymic stromal cells that mediate the negative and positive selection of the T-cell repertoire. Previous work has pointed to a bone-marrow-derived macrophage or dendritic cell as the inducer of tolerance, whereas a radiation-resistant, deoxyguanosine-resistant thymic cell seems to mediate the positive selection of self-MHC restricted T cells. Thymic stromal cells in the cortex interact with the T-cell antigen receptor on thymocytes. Using several strains of transgenic mice that express the class II MHC molecule I-E in specific regions of the thymus, we show directly that the positive selection of T cells is mediated by an I-E-bearing cell in the thymic cortex.

Animals↗
PubMed2005

Aberrant methylation: common in thymic carcinomas, rare in thymomas.

Thymic carcinoma, which is a rare epithelial neoplasm of the thymus gland, is different from thymoma in its clinical and pathological features. To clarify the mechanism underlying the aggressive behavior of thymic carcinoma, we examined the clinicopathologic features, aberrant methylation patterns of the tumor suppressor genes, and epidermal growth factor receptor (EGFRs) mutation in both thymic carcinomas and thymomas. Clinical data of 11 thymic cancers and 13 thymomas were reviewed. Resected samples of 5 thymic cancers and 6 thymomas selected from 24 cases were used for methylation and mutation studies. Positive tumor markers were more frequent in thymic cancers than in thymomas (p=0.0233), and the methylation index, which reflects the overall methylation pattern, was significantly higher in thymic carcinomas (p=0.0053). No tumors showed a mutation of EGFR, KRAS, and HER2. Thymic carcinoma is distinct from thymoma not only with respect to clinicopathological features, but also aberrant methylation patterns of the tumor suppressor genes.

Adult↗
PubMed1997

Discrimination between maintenance- and differentiation-inducing signals during initial and intermediate stages of positive selection.

As well as signaling through the alphabeta T cell receptor complex, positive selection of immature CD4+ 8+ thymocytes involves additional ill-defined accessory interactions provided by thymic epithelial cells. Here, we have isolated CD4+ 8+ thymocytes at a pre-positive selection stage of development (TCR- CD69- 4+ 8+ cells), or after initiation of positive selection (CD69+ 4+ 8+ cells), from mice where the normal lifespan of thymocytes is extended by the presence of a bcl-2 transgene, to allow us to discriminate between requirements for maintenance and differentiation signals during positive selection. We find that MHC class II+ thymic epithelial cells drive positive selection of TCR- CD69- 4+ 8+ bcl-2 tg thymocytes to the CD4+ and CD8+ stage, while no such mature subsets are observed when thymocytes are cultured alone or with major histocompatibility complex (MHC) class II+ salivary epithelial cells. However, CD4+ 8+ cells remain in such cultures in considerable numbers, and retain the potential for positive selection if re-cultured with thymic epithelium, suggesting that thymic epithelial cells provide specific differentiation-inducing signals for positive selection. In contrast, intermediate CD69+ 4+ 8+ thymocytes show some capacity for phenotypic conversion in the absence of thymic stromal cells although strikingly the single-positive CD4+ and CD8+ cells generated are not functionally competent. Finally, we show that prior culture of thymic epithelial cells under monolayer conditions abrogates their ability to support the initiation of positive selection, suggesting that the epithelial cell molecules necessary for the provision of differentiation signals during positive selection are down-regulated under such conditions.

Animals↗
PubMed2000

Degree of ERK activation influences both positive and negative thymocyte selection.

Considerable evidence suggests that the ERK pathway is required for positive but not negative thymocyte selection. Here, we report that ERK is highly activated in double-positive (DP) thymocytes expressing an MHC class I-restricted TCR (P14) in response to negatively selecting conditions, whereas ligands that trigger positive selection induced weaker ERK activation. Biochemical evidence also shows that death by neglect is associated with a further reduction in ERK activation. These findings are consistent with the affinity / avidity model of thymocyte selection. To further examine the role of ERK in negative selection we used the MEK-1 inhitibor, PD98059, a specific pharmacological inhibitor of the ERK pathway. Biochemical data demonstrated a reduction of ERK activity by PD98059 in the presence of the negatively selecting ligand. Analysis of P14 TCR-transgenic fetal thymic lobes cultured with PD98059 under negatively selecting conditions showed impaired clonal deletion of DP thymocytes and a concomitant increase in positive selection of functional mature, TCR(hi) transgenic T cells. This demonstrates that altering ERK activity switched negative to positive selection. Contrary to previous reports that show an exclusive role for ERK signaling in positive selection, our data demonstrate that negative selection is also sensitive to the degree of ERK activation.

Animals↗
PubMed1995

Therapeutic effect of early thymic irradiation in (NZB x NZW)F1 mice, associated with a selective decrease in the levels of IgG3 and gp70-anti-gp70 immune complexes.

The lupus-prone (NZB x NZW)F1 female mice (NZB/W) develop an autoimmune disease characterized by production of autoAb and fatal glomerulonephritis. Since it has been previously shown that total lymphoid irradiation has a beneficial effect in this model, we have analyzed whether early thymic irradiation (ETI) could improve the course of the lupus-like syndrome in these mice. NZB/W mice received thymic irradiation (4500 rads) beginning at 10 weeks of age, prior to the onset of autoimmune manifestations. Then, they were evaluated for survival, renal histology, and serological markers of autoimmunity, in comparison to nonirradiated NZB/W females. The treatment with ETI improved nephritis and survival in NZB/W mice: 50% mortality was observed at 12 months in irradiated mice and at 9 months in untreated mice. This improved survival could not be attributed to a reduction in the titers of anti-dsDNA Ab nor in the levels of total immune complexes which were essentially identical in both groups. By contrast, this improvement was related to a selective normalization in the serum levels of IgG3 and gp70-anti-gp70 immune complexes (gp70IC) in ETI NZB/W female mice as compared to that seen in nonirradiated NZB/W females. These data show the therapeutical effect of ETI and support the pathogenic role of IgG3 and gp70IC in the development of glomerulonephritis in NZB/W mice.

Animals↗
PubMed1980

Serum thymic factor activity in deficiencies of calories, zinc, vitamin A and pyridoxine.

Cell-mediated immunity is invariably impaired in protein-energy malnutrition. The effect of selected nutrient deficiencies on serum thymic factor activity was assessed in deprived rats and pair-fed controls. Deficits of calories, zinc or pyridoxine resulted in significant lowering of serum thymic factor activity whereas vitamin A deficiency did not have any effect. It is suggested that variants nutrients modulate different steps of cell-mediated immunity and that reduced thymic hormone activity may be the underlying mechanism of imparied immunity in some but not all nutritional deficiencies.

Animals↗
PubMed1990

Selective expression of CD8 alpha (Ly-2) subunit on activated thymic gamma/delta cells.

Although most cells of the T cell receptor (TcR) gamma/delta lineage are CD4-CD8-, some gamma/delta cells express CD8. We show here that mouse thymic gamma/delta cells express CD8 following in vitro activation by concanavalin A. Staining with monoclonal and polyclonal antibodies to the CD8 alpha (Ly-2) and CD8 beta (Ly-3) subunits indicates that only CD8 alpha is expressed by these activated TcR gamma/delta cells. Furthermore, immunoprecipitation and reduced/nonreduced gel analysis reveals that thymic gamma/delta cells express CD8 alpha as a homodimer. In contrast, similarly activated TcR alpha/beta cells express a conventional CD8 alpha/CD8 beta heterodimer.

Animals↗
PubMed1995

Cryptocrine signaling in the thymus network and T cell education to neuroendocrine self-antigens.

Both during phylogeny and ontogeny the thymus appears as a nodal point between the two major systems of cell-to-cell signaling, the neuroendocrine and immune systems. This review presents the experimental observations which support a dual role in T cell selection played by the thymic repertoire of neuroendocrine polypeptide precursors. Through the mode of cryptocrine intercellular signaling thymic neuroendocrine-related precursors synthesized in thymic epithelial cells have been shown to influence the early steps in T cell differentiation. In addition, thymic neuroendocrine-related polypeptides are a source of self-antigens which are presented by the major histocompatibility system of the thymic epithelium. Preliminary data also suggest that the intrathymic T cell education to neuroendocrine self-antigens is not strictly superimposible to the antigen presentation by dedicated presenting cells. Insulin-like growth factor-II (IGF-II) was identified as one dominant member of the insulin family expressed by thymic epithelial and nurse cells. The intrathymic presentation of IGF-II or IGF-II derived self-antigens is under current investigation. If further confirmed, the central tolerogenic properties of IGF-II could be considered in the elaboration of a strategy for an efficient and safe prevention of insulin-dependent diabetes.

Amino Acid Sequence↗
PubMed1998

The human thymus. A chimeric organ comprised of central and peripheral lymphoid components.

The human thymus is a lymphoepithelial organ in which T cells develop during fetal life. After maturation and selection in the fetal thymic microenvironment, T cells emigrate to peripheral lymphoid tissues such as the spleen, gut, and lymph nodes, and establish the peripheral T cell repertoire. Although the thymus has enormous regenerative capacity during fetal development, the regenerative capacity of the human postnatal thymus decreases over time. With the advent of intensive chemotherapy regimens for a variety of cancer syndromes, and the discovery that infection with the Human Immunodeficiency Virus (HIV) leads to severe loss of CD4+ T cells, has come the need to understand the role of the human thymus in reconstitution of the immune system in adults. During a recent study of the thymus in HIV infection, we observed many CD8+ T cells in AIDS thymuses that had markers consistent with those of mature effector cytotoxic T cells usually found in peripheral immune tissues, and noted these CD8+ effector T cells were predominately located in a thymic zone termed the thymic perivascular space. This article reviews our own work on the thymus in HIV-1 infection, and discusses the work of others that, taken together, suggest that the thymus contains peripheral immune cell components not only in the setting of HIV infection, but also in myasthenia gravis, as well as throughout normal life during the process of thymus involution. Thus, the human thymus can be thought of as a chimeric organ comprised of both central and peripheral lymphoid tissues. These observations have led us to postulate that the thymic epithelial atrophy and decrease in thymopoiesis that occurs in myasthenia gravis, HIV-1 infection, and thymic involution may in part derive from cytokines or other factors produced by peripheral immune cells within the thymic perivascular space.

Adult↗
PubMed1998

The human thymus. A chimeric organ comprised of central and peripheral lymphoid components.

The human thymus is a lymphoepithelial organ in which T cells develop during fetal life. After maturation and selection in the fetal thymic microenvironment, T cells emigrate to peripheral lymphoid tissues such as the spleen, gut, and lymph nodes, and establish the peripheral T cell repertoire. Although the thymus has enormous regenerative capacity during fetal development, the regenerative capacity of the human postnatal thymus decreases over time. With the advent of intensive chemotherapy regimens for a variety of cancer syndromes, and the discovery that infection with the Human Immunodeficiency Virus (HIV) leads to severe loss of CD4+ T cells, has come the need to understand the role of the human thymus in reconstitution of the immune system in adults. During a recent study of the thymus in HIV infection, we observed many CD8+ T cells in AIDS thymuses that had markers consistent with those of mature effector cytotoxic T cells usually found in peripheral immune tissues, and noted these CD8+ effector T cells were predominantly located in a thymic zone termed the thymic perivascular space. This article reviews our own work on the thymus in HIV-1 infection, and discusses the work of others that, taken together, suggest that the thymus contains peripheral immune cell components not only in the setting of HIV infection, but also in myasthenia gravis, as well as throughout normal life during the process of thymus involution. Thus, the human thymus can be thought of as a chimeric organ comprised of both central and peripheral lymphoid tissues. These observations have led us to postulate that the thymic epithelial atrophy and decrease in thymopoiesis that occurs in myasthenia gravis, HIV-1 infection, and thymic involution may in part derive from cytokines or other factors produced by peripheral immune cells within the thymic perivascular space.

Adult↗
PubMed2006

Regulatory T cells in microbial infection.

Natural T regulatory cells (NatTReg) limit immunopathology and protective immune responses induced upon microbial infection. In addition, infection increases the number and activity of NatTReg. These findings need to be conciliated with the process of 'self-nonself' discrimination based on the function of NatTReg committed intrathymically and positively selected (and activated) on thymic epithelial cells. A review of the available evidence comforts the assumptions that, in physiological conditions, NatTReg engaged in the immune responses to microbial infections are drawn from the autoreactive repertoire even if some may appear to be microbe specific. This contention also provides a suitable explanation for the 'hygiene hypothesis': infections re-enforce the physiological mechanisms of natural dominant tolerance, through the expansion of naturally occurring regulatory T cells. Accumulating evidence demonstrates that pro-inflammatory ligands of Toll-like receptors expressed by NatTReg, both of microbial (e.g., lipopolysaccharide, flagellin, peptidoglycans) and endogenous (e.g., stress proteins and degradation products of the extracellular matrix) origin, may play a critical role in their activation and expansion. As NatTReg vigorously respond to IL-2/IL-15 locally produced by ongoing effector responses, this whole set of mechanisms provides for a robust feedback process that limits tissue damage and accounts for an 'organism-centered' quality control of immune responses. Detailed knowledge on these molecular and cellular bases should open novel opportunities for intervention in a variety of critical conditions, such as autoimmunity, allergy, chronic infections, and cancer, for which we currently lack effective therapies.

Animals↗
PubMed1981

Proton NMR investigation of Ln3+ complexes of thymopoietin 32-36.

The pentapeptide Arg-Lys-Asp-Val-Tyr (TP5) is a biologically active fragment of thymopoietin, the thymic hormone that induces selective T-cell differentiation. The formation of lanthanide(III) complexes of TP5 is demonstrated through the observation of Tb3+ fluorescence enhancement. The equilibria, stoichiometry and solution conformation of the La3+, Pr3+ and Yb3+ complexes of TP5 have been investigated using NMR spectroscopy. In addition, the dissociation constants of two methyl ester analogs of TP5 have been studied. Evidence is presented supporting an interaction between the arginine guanidino N epsilon H and the aspartate carboxylate of TP5. Binding of Ln3+ appears to be accompanied by a disruption (or weakening) of this interaction and a concomitant increase in the 180 degrees rotamer population for the aspartate carboxylate group. The observed trends in the magnitudes of the dissociation constants and the rotamer populations appear to suggest that, although a significant amount of monodentate complexes may also exist, the metal ion binds predominantly to both carboxylates in a bidentate fashion.

Amino Acids↗
PubMed1999

Inhibition of Rho at different stages of thymocyte development gives different perspectives on Rho function.

Development of thymocytes can be staged according to the levels of expression of the cell-surface markers CD4, CD8, CD44, CD25 and CD2. Thymocyte development is regulated by a complex signalling network [1], one component of which is the GTPase Rho. The bacterial enzyme C3 transferase from Clostridium botulinum selectively ADP-ribosylates Rho in its effector-binding domain and thereby abolishes its biological function [2,3]. To explore the function of Rho in thymocyte development, we previously used the proximal promoter of the gene encoding the Src-family kinase p56lck to make transgenic mice that selectively express C3 transferase in the thymus [4,6]. In these mice, which lack Rho function from the earliest thymocyte stages, thymocyte numbers are reduced by approximately 50- to 100-fold. Here, we describe transgenic mice that express C3 transferase under the control of the locus control region (LCR) of the CD2 gene; this regulatory element drives expression at a later stage of thymocyte development than the lck proximal promoter [7]. In these mice, thymocyte numbers were also reduced by 50- to 100-fold, but unlike the lck-C3 mice, in which the reduction predominantly results from defects in cell survival of CD25(+) thymocyte progenitors, the CD2-C3 transgenic mice had a pre-T-cell differentiation block at the CD25(+) stage after rearrangement of the T-cell receptor (TCR) beta chains. Analysis of CD2-C3 mice demonstrated that Rho acts as an intracellular switch for TCR beta selection, the critical thymic-differentiation checkpoint. These results show that Rho-mediated survival signals for CD25(+) pre-T cells are generated by the extracellular signals that act on earlier thymocyte precursors and also that temporal cell-type-specific elimination of Rho can reveal different functions of this GTPase in vivo.

ADP Ribose Transferases↗
PubMed2000

A specific interferon (IFN)-stimulated response element of the distal HLA-G promoter binds IFN-regulatory factor 1 and mediates enhancement of this nonclassical class I gene by IFN-beta.

Type I interferons display a broad range of immunomodulatory functions. Interferon beta increases gene expression at the transcriptional level through binding of factors to the interferon-stimulated response element (ISRE) within the promoters of interferon-inducible genes, such as HLA class I. Despite mutation of the class I ISRE sequence within the nonclassical HLA-G class I gene promoter, we show that interferon beta enhances both transcription and cell surface expression of HLA-G in trophoblasts and amniotic and thymic epithelial cells that selectively express it in vivo. Deletion and mutagenesis analysis of a putative interferon-regulatory factor (IRF)-1 binding site within the HLA-G promoter show that HLA-G transactivation is mediated through an ISRE sequence 746 base pairs upstream from ATG, which is distinct from the interferon-responsive element described within proximal classical class I gene promoters. Electrophoretic mobility shift analysis and supershift analysis further demonstrate that interferon-responsive transcription factors, including IRF-1, specifically bind to the HLA-G ISRE. Our results provide evidence that IRF-1 binding to a functional ISRE within the HLA-G promoter mediates interferon beta-induced expression of the HLA-G gene. These observations are of general interest considering the implication of HLA-G in mechanisms of immune escape involved in fetal-maternal tolerance and other immune privilege situations.

Amnion↗