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Results for “thymic selection”

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PubMed2003

CD1d-expressing dendritic cells but not thymic epithelial cells can mediate negative selection of NKT cells.

Natural killer T (NKT) cells are a unique immunoregulatory T cell population that is positively selected by CD1d-expressing thymocytes. Previous studies have shown that NKT cells exhibit autoreactivity, which raises the question of whether they are subject to negative selection. Here, we report that the addition of agonist glycolipid alpha-galactosylceramide (alpha-GalCer) to a fetal thymic organ culture (FTOC) induces a dose-dependent disappearance of NKT cells, suggesting that NKT cells are susceptible to negative selection. Overexpression of CD1d in transgenic (Tg) mice results in reduced numbers of NKT cells, and the residual NKT cells in CD1d-Tg mice exhibit both an altered Vbeta usage and a reduced sensitivity to antigen. Furthermore, bone marrow (BM) chimeras between Tg and WT mice reveal that CD1d-expressing BM-derived dendritic cells, but not thymic epithelial cells, mediate the efficient negative selection of NKT cells. Thus, our data suggest that NKT cells developmentally undergo negative selection when engaged by high-avidity antigen or abundant self-antigen.

Animals↗
PubMed2003

Vaccination with myelin oligodendrocyte glycoprotein adsorbed to alum effectively protects DBA/1 mice from experimental autoimmune encephalomyelitis.

To prevent an organism from developing autoimmunity the body limits the number of autoreactive cells through thymic negative selection and regulates their activity through induction of suppressor T cells. Development of antigen-specific therapies provides an interesting opportunity to imitate the body's own, often effective, method of protection. Our study demonstrates that DBA/1 mice could be protected from experimental autoimmune encephalomyelitis induced through injection of recombinant myelin oligodendrocyte glycoprotein (rMOG) when they were previously immunized intraperitoneally with rMOG adsorbed to aluminium hydroxide. This protection was associated with a decreased IFN-gamma production by rMOG-specific cells, but not a decreased proliferative response. Protection was long lasting, indicating that MOG-alum vaccination might be developed as a prophylactic therapy in multiple sclerosis.

Adjuvants, Immunologic↗
PubMed1995

Antigen-receptor induced clonal expansion and deletion of lymphocytes are impaired in mice lacking HS1 protein, a substrate of the antigen-receptor-coupled tyrosine kinases.

HS1, an intracellular protein expressed specifically in hematopoietic cells, is rapidly tyrosine phosphorylated after cross-linking of antigen receptors on B and T lymphocytes, implicating involvement of this molecule in the signal transduction pathways from the antigen receptors as a substrate of membrane-associated tyrosine kinase(s). The development of lymphoid cells in HS1-deficient mice, generated through gene targeting, appeared normal. However, antibody production to T-independent antigen and proliferative responses of splenic B and T cells after cross-linking of the antigen receptors were impaired in these mutant mice. Furthermore, B cells in the peritoneal cavity of the mutant mice were resistant to multivalent cross-linking of the antigen receptor, which causes apoptosis of such cells in normal mice. Crossing the HS1-deficient mice with the mice harboring transgenes encoding alpha and beta chains of T-cell antigen receptor against a male H-Y antigen resulted in a progeny that demonstrated a significantly impaired ability of thymic negative selection. These results indicate that HS1 is a novel molecule involved in the antigen-receptor-derived signaling pathways and plays important roles not only in clonal expansion, but also in clonal deletion of B and T cells.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Heterogeneity in the clonal T cell response. Implications for models of T cell activation and cytokine phenotype development.

The T cell can be defined in the context of two properties--the recognition specificity of the T cell receptor (TCR) heterodimer and the functional response of the T cell after TCR stimulation. Once a particular TCR heterodimer is expressed and successfully selected during thymic development, the antigen specificity is fixed for all the clonal progeny of that cell. In contrast, the potential functional responses that may be generated in response to specific antigen in the postthymic environment are quite extensive. These range from programmed cell death to initiation of alternate programs of phenotype development that generate effector populations with distinct cytokine expression patterns and regulatory properties. Recent advances in analytical methods that have permitted multiparametric characterizations of the T cell response at the single cell, rather than population level, have necessitated a modified view of T cell activation and the clonal T cell response, and have generated new insights into the regulation of immunity. In this brief review, we highlight studies that have characterized heterogeneity of the CD4+ T cell clonal response based on single-cell analyses, and discuss implications for models of T cell activation and cytokine phenotype development.

Animals↗
PubMed2006

Metallophilic macrophages are lacking in the thymus of lymphotoxin-beta receptor-deficient mice.

Lymphotoxin-beta receptor (LTbetaR) axis plays a crucial role in development and compartmentalization of peripheral lymphatic organs. But, it is also required for the appropriate function and maintenance of structural integrity of the thymus: in LTbetaR-deficient animals the clonal deletion of autoreactive lymphocytes is impaired and differentiation of thymic medullary epithelial cells is disturbed. In this study, using several markers, we showed that thymic metallophilic macrophages were lacking in LTbetaR-deficient mice. In tumor necrosis factor receptor-I (p55)-deficient mice (which we used as positive control) thymic metallophilic cells were located, similarly as in normal mice, in the thymic cortico-medullary zone at the junction of cortex and medulla. These findings show that LTbetaR is necessary for maintenance of metallophilic macrophages in the thymus and provide further evidence that these cells may represent a factor involved in thymic negative selection.

Animals↗
PubMed1986

Tissue origin of serum placental-like alkaline phosphatase in cigarette smokers.

A variety of solubilised tissue extracts from cigarette smokers and non-smokers have been screened quantitatively for both placental alkaline phosphatase (PLAP) and placental-like alkaline phosphatase (PLAP-like AP) in order to identify the possible tissue origins of the circulating PLAP-like AP found in most smokers. Lung alveolar tissue, and to a lesser extent colonic tissues, contained both PLAP-like AP and PLAP. Tissues from smokers and non-smokers contained comparable proportions and amounts of PLAP and PLAP-like AP. No other tissue source of PLAP-like AP was found other than those previously reported for testicular, endometrial and thymic tissue. Selective release of PLAP-like AP from the lung in cigarette smokers seems likely to be a major source for this isoenzyme in peripheral circulation.

Alkaline Phosphatase↗
PubMed1989

Do CD4 and CD8 control T-cell activation via a specific tyrosine protein kinase?

The CD4 and CD8 glycoproteins play an important role in T-cell activation by binding to major histocompatibility complex (MHC) class II or class I molecules, respectively, and stabilizing their interactions with the T-cell receptor-CD3 complex during antigen presentation. Recent evidence suggesting that the cytoplasmic domains of CD4 and CD8 are physically, and perhaps functionally, linked to the T-cell specific tyrosine protein kinase, p56lck, adds a new dimension to our current understanding of their physiological function. Based on these and other recent findings, Tomas Mustelin and Amnon Altman present a working hypothesis that defines a novel role for CD4 or CD8 in regulating T-cell activation, and perhaps other processes, such as thymic repertoire selection and human immunodeficiency virus (HIV)-induced immunosuppression.

Animals↗
PubMed1992

The blood group antigen-related glycoepitopes: key structural determinants in immunogenesis and AIDS pathogenesis.

This overview will focus on the functional and pathophysiological aspects of blood group antigen (BGA)-related glycodeterminants with regard to immunogenesis and AIDS pathogenesis. It has been postulated that in a broad range of histogenetically different tissues and organs, BGA-related glycoepitopes are expressed on the cell surface at definite stages of cell differentiation. These glycoepitopes are expressed during embryogenesis, organogenesis, tissue repair, regeneration, remodelling and maturation when 'sorting-out' of one homotypic cell population from a heterotypic assemblage of cells occurs (1). In this event, the BGA-related glycoepitopes, if being expressed on the cell surface, play roles of key structural determinants in cell-cell recognition, association and aggregation. This mechanism will be discussed in relation to immunogenesis with regard to antigen presentation, self-non-self discrimination, and positive and negative selection during thymic education. It is postulated that the appearance of BGA-related glycoepitopes on the cell membrane is a consequence of the association of major histocompatibility complex antigens (MHC) and peptides, with the subsequent elimination of cells carrying a high density of BGA-related glycoepitopes on their surface. After human immunodeficiency virus (HIV) glycoproteins are glycosylated by host cell glycosyltransferases, the virus may use the BGA-related glycodeterminants as ligands and/or receptors for expansion to a spectrum of target cells during AIDS development and generalization of the infection throughout the body. We will review the experimental evidence that supports the concept that HIV uses an alternative to the gp120/CD4 ligand/receptor system, and that the alternative mechanism is probably carbohydrate-mediated in nature.

Acquired Immunodeficiency Syndrome↗
PubMed1992

The blood group antigens (BGA)-related glycoepitopes. A key structural determinant in immunogenesis and cancer pathogenesis.

This overview has been focused on the functional and pathophysiological aspects of blood group antigens (BGA)-related glycodeterminants. It has been postulated that in a broad range of histogenetically different tissues and organs BGA-related glycoepitopes are expressed on the cell surface at definite stages of cell differentiation during embryogenesis, organogenesis, tissue repair, regeneration, remodeling and maturation when 'sorting-out' behaviour of one homotypic cell population from heterotypic assemblage of cells occurs. In this event the BGA-related glycoepitopes, if being expressed on the cell surface, play a role of key structural determinants in cell-cell recognition, association and aggregation. This mechanisms has been discussed in relation to immunogenesis regarding of antigen presentation, self-non-self discrimination, positive and negative selection during thymic education. It is postulated that the appearance of the BGA-related glycoepitopes on the cell membrane is a consequence of the association of MHC and peptides, with subsequent elimination of cells carring high density of BGA-related glycoepitopes on their surface. In cancer it has been considered as a key mechanism of phenotypic divergence of tumor cells, immunoselection, tumor progression and metastasis.

Blood Group Antigens↗
PubMed2006

Establishment of the major compatibility complex-dependent development of CD4+ and CD8+ T cells by the Cbl family proteins.

Casitas B cell lymphoma (Cbl) proteins are negative regulators for T cell antigen receptor (TCR) signaling. Their role in thymocyte development remains unclear. Here we show that simultaneous inactivation of c-Cbl and Cbl-b in thymocytes enhanced thymic negative selection and altered the ratio of CD4(+) and CD8(+) T cells. Strikingly, the mutant thymocytes developed into CD4(+)- and CD8(+)-lineage T cells independent of the major histocompatibility complex (MHC), indicating that the CD4(+)- and CD8(+)-lineage development programs are constitutively active in the absence of c-Cbl and Cbl-b. The mutant double-positive (DP) thymocytes exhibited spontaneous hyperactivation of nuclear factor-kappa B (NF-kappaB). Additionally, they failed to downregulate the pre-TCR and pre-TCR signaling. Thus, our data indicate that Cbl proteins play a critical role in establishing the MHC-dependent CD4(+) and CD8(+) T cell development programs. They likely do so by suppressing MHC-independent NF-kappaB activation, possibly through downmodulating pre-TCR signaling in DP thymocytes.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Lymphocyte apoptosis as an immune subversion strategy of microbial pathogens.

Apoptosis is a component of cellular death in several immunological reactions. Lymphocyte apoptosis is a feature of negative selection of thymic lymphocytes. Target cells die by apoptosis during their interaction with cytotoxic T cells. Antigens derived from apoptotic cells can be cross-presented by antigen presenting cells (APCs). In these examples, apoptotic death is a beneficial feature for the individual. The apoptosis of cells also occurs during infection with a variety of microorganisms, but this process can be detrimental to the handling of the infection by the host. Here, we aim to highlight some of the recent advances in understanding why apoptosis can be a detrimental event during infection. We will focus on recent research with the intracellular bacterial pathogen Listeria monocytogenes, which demonstrates how apoptosis is induced, some of the host pathways that are exploited and the immunological consequences of cell death. We propose that L. monocytogenes causes lymphocyte death by enhancing the cell-death programs of the host. The presence of apoptotic lymphocytes downregulates early innate immunity, creating a permissive environment for bacterial growth.

Animals↗
PubMed2004

Development of autoreactive diabetogenic T cells in the thymus of NOD mice.

Type 1 diabetes results from destruction of pancreatic beta cells by beta cell-specific autoreactive T cells in the nonobese diabetic (NOD) mouse. Defects in thymic negative selection are thought to result in failure to delete potential beta cell-reactive T cells, contributing to the development of autoimmune diabetes. We investigated this possibility by comparing the deletion profile of double-positive (DP) thymocytes in NOD mice with diabetes-resistant strains of mice after anti-CD3 Ab treatment to trigger the TCR-mediated signaling pathway. We found that immature NOD CD4+CD8+ DP thymocytes have a lower activation threshold than C57BL/6 and Balb/c thymocytes. This was confirmed by showing that NOD DP thymocytes have a higher level of ERK and JNK phosphorylation. The low activation threshold of immature thymocytes resulted in rapid deletion of strongly activated immature DP thymocytes by negative selection, whereas weakly activated immature thymocytes differentiated more efficiently into CD69+CD3high DP thymocytes by positive selection. SP thymocytes, particularly CD4-CD8+ T cells that were efficiently generated from activated DP thymocytes, could induce severe insulitis and diabetes in NOD.scid mice. We conclude that the development of autoreactive diabetogenic T cells results from inordinate positive selection due to the low activation threshold of DP thymocytes in NOD mice.

Animals↗
PubMed2000

Vitamin E and immunity.

Vitamin E is a potent antioxidant and has an ability to modulate host immune functions. This chapter consists of five parts: (1) vitamin E deficiency and immunity, (2) vitamin E supplementation and immunity, (3) vitamin E and the decreased cellular immunity with aging, (4) vitamin E and T-cell differentiation in the thymus, and (5) vitamin E and acquired immune deficiency syndrome (AIDS). In vitamin E deficiency most of the immune parameters show a downward trend, which is associated with increased infectious diseases and the incidence of tumors. In contrast, vitamin E supplementation has various beneficial effects on the host immune system. The decreased cellular immunity with aging or during the development of AIDS is markedly improved by the intake of a high vitamin E diet. In addition, vitamin E plays an important role in the differentiation of immature T cells in thymus. Vitamin E deficiency induces the decreased differentiation of immature T cells, which results in the early decrease of cellular immunity with aging in spontaneously hypertensive rats. Conversely, vitamin E supplementation induces a higher differentiation of immature T cells via increased positive selection by thymic epithelial cells, which results in the improvement of decreased cellular immunity in the aged. Furthermore, vitamin E supplementation induces the early recovery of thymic atrophy following X-ray irradiation. Taken together, these results suggest that vitamin E is an important nutrient for maintaining the immune system, especially in the aged.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Vav1-deficient mice are resistant to MOG-induced experimental autoimmune encephalomyelitis due to impaired antigen priming.

Mice that lack the guanine nucleotide exchange factor (GEF) Vav1 exhibit particular defects in antigen-triggered T cell activation but may have an autoreactive T cell repertoire due to impaired intra-thymic negative selection. MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE) was used to test the susceptibility of Vav1(-/-) mice to organ-specific autoimmunity. Vav1(-/-) animals were found to be resistant to MOG(35-55)-EAE since the priming and in vivo expansion of myelin oligodendrocyte glycoprotein (MOG)-specific T cells was inefficient despite fully functional antigen presentation. Protection from cell-mediated autoimmunity was not due to a Th2 bias, to the lack of IL-2 or a failure of Vav1(-/-) T cells in terms of chemotactic mobility.

Animals↗
PubMed1997

Antigen processing differences among APC.

The hierarchy of display of determinants on a protein antigen is of critical importance with respect to which T cells will be selected during thymic development, as well as in the induction of mature responses. Activation of T cells will be dependent on unfolding, reduction and chain cleavage of the antigen, and the vagaries of competition with other determinants as well as hindrance in access to the major histocompatibility complex (MHC) or subsequently of the MHC/peptide complex to the T cell receptor. We here focus on a description of the parameters that determine the generation and display of determinants on MHC class II molecules by different types of antigen presenting cells in different locations.

Antigen Presentation↗
PubMed2001

The instructive role of dendritic cells on T cell responses: lineages, plasticity and kinetics.

Dendritic cells are responsible for directing different types of T cell responses, from thymic negative selection to the generation of effector and memory cells and the induction of peripheral tolerance. Recent studies indicate that the dendritic cell lineage, the extent of recruitment into inflamed tissues and migration to lymph nodes, the nature of maturation stimuli and the kinetics of activation have a quantitative and qualitative impact on T cell stimulation, thus exerting an instructive control on T cell responses.

Animals↗
PubMed2001

T cell-specific loss of Pten leads to defects in central and peripheral tolerance.

PTEN, a tumor suppressor gene, is essential for embryogenesis. We used the Cre-loxP system to generate a T cell-specific deletion of the Pten gene (Pten(flox/-) mice). All Pten(flox/-) mice develop CD4+ T cell lymphomas by 17 weeks. Pten(flox/-) mice show increased thymic cellularity due in part to a defect in thymic negative selection. Pten(flox/-) mice exhibit elevated levels of B cells and CD4+ T cells in the periphery, spontaneous activation of CD4+ T cells, autoantibody production, and hypergammaglobulinemia. Pten(flox/-) T cells hyperproliferate, are autoreactive, secrete increased levels of Th1/Th2 cytokines, resist apoptosis, and show increased phosphorylation of PKB/Akt and ERK. Peripheral tolerance to SEB is also impaired in Pten(flox/-) mice. PTEN is thus an important regulator of T cell homeostasis and self-tolerance.

Animals↗
PubMed2002

About CD4pos CD25pos regulatory cells.

Autoreactive cells that escape from thymic negative selection are either anergized or counter-regulated in the peripheral lymphoid organs by regulatory T (Treg) cells. Most investigated Treg cells are CD4pos cells expressing the alpha chain of the IL-2 receptor (CD25). Absence of this particular population leads to the development of a wide range of autoimmune disorders, suggesting a critical role for CD4pos CD25pos cells in the maintenance of normal immune homeostasis. Numerous studies have aimed at unraveling the mechanisms of regulation, focusing mainly on naturally occurring Treg cells (generated in naive animals) and regulation of CD4pos autoreactive cells. In contrast, generation following antigenic priming of CD4pos CD25pos Treg cells with non-self (viral) antigen specificity and regulation of virus-activated CD4pos and CD8pos cells remain to be investigated. In this review, we describe the data collected over the past few years of intense focus on CD4pos CD25pos Treg cells and present our approach to investigate the generation of antigen-specific Treg cells during the course of an anti-viral immune response.

Animals↗