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PubMed1988

Dibutyltin and tributyltin compounds induce thymus atrophy in rats due to a selective action on thymic lymphoblasts.

Di-n-butyltin dichloride (DBTC) or tri-n-butyltin chloride (TBTC) given in the diets of rats have previously been shown to cause atrophy of the thymus and subsequently suppression of the T-cell-dependent immune responses. To study the mechanism of the immunotoxic effects, the dose-effect relationships and the kinetics of the thymus atrophy caused by DBTC and TBTC were investigated in detail. A single oral dose of DBTC or TBTC to rats induced a dose-related reduction of relative thymus weight, which was maximal 4 days after intubation. The log dose-effect relationships for both compounds were linear and ran parallel over a dose range of 5-60 mg/kg. Dose levels calculated to cause 50% reduction of relative thymus weight were 18 mg DBTC and 29 mg TBTC per kg body wt. A single oral dose of mono-n-butyltin trichloride (MBTC), however, did not cause thymus atrophy at dose levels up to 180 mg/kg. The kinetics of the dibutyltin- and tributyltin-induced thymus atrophy in rats were investigated by measuring thymus weight, total thymic cell count, number of small, intermediate and large cells and the incorporation of DNA, RNA and protein precursors into isolated thymocytes during a period of 9 days after a single oral dose. DBTC and TBTC caused atrophy of the thymus due to a selective reduction in the number of rapidly proliferating lymphoblasts in the first 2 days after dosing. As a consequence the large pool of small lymphocytes declined in the following 2 days. On the fourth day, when atrophy was most pronounced, the frequency of the lymphoblasts increased above the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1999

Using thymus anatomy to dissect T cell repertoire selection.

The thymic development of CD4(+) T cells incorporates the opposing processes of positive and negative selection to produce mature lymphocytes which respond to foreign peptides in the context of self-major histocompatibility complex class II molecules. Here, we present a model in which these events occur in two temporally and anatomically distinct steps. We propose that an initial positive selection step is mediated exclusively by thymic cortical epithelium. Subsequently, all those thymocytes which have been positively selected will interact with medullary epithelium and bone marrow-derived cells. Those thymocytes reacting with excess affinity or avidity to these antigen presenting cells will be negatively selected. Although acknowledging the importance of differential signalling to the developing thymocyte, we will emphasize the centrality of the phenotype of the tissues which comprise the thymus.

Animals↗
PubMed1995

Lymphocytes selected in allogeneic thymic epithelium mediate dominant tolerance toward tissue grafts of the thymic epithelium haplotype.

Athymic mice grafted at birth with allogeneic thymic epithelium (TE) from day 10 embryos before hematopoietic cell colonization reconstitute normal numbers of T cells and exhibit full life-long tolerance to skin grafts of the TE haplotype. Intravenous transfers of splenic cells, from these animals to adult syngeneic athymic recipients, reconstitute T-cell compartments and the ability to reject third-party skin grafts. The transfer of specific tolerance to skin grafts of the TE donor strain, however, is not observed in all reconstituted recipients, and the fraction of nontolerant recipients increases with decreasing numbers of cells transferred. Furthermore, transfers of high numbers of total or CD4+ T cells from TE chimeras to T-cell receptor-anti-H-Y antigen transgenic immunocompetent syngeneic hosts specifically hinder the rejection of skin grafts of the TE haplotype that normally occurs in such recipients. These observations demonstrate (i) that mice tolerized by allogeneic TE and bearing healthy skin grafts harbor peripheral immunocompetent T cells capable of rejecting this very same graft; and (ii) that TE selects for regulatory T cells that can inhibit effector activities of graft-reactive cells.

Animals↗
PubMedDate not supplied

Thymic stromal cells and positive selection.

The intrathymic differentiation events leading to the development and export of mature T cells tolerant to self yet capable of responding to foreign peptide antigen in the context of self-MHC are clearly both dynamic and complex. The changing phenotype of the developing thymocyte as it migrates through and interacts with the heterogeneous thymic microenvironment and the intracellular signalling events associated with such interactions are being extensively studied, yet many aspects remain poorly defined, such as the precise relationship between stromal cells and thymic selection. Positive and negative selection are crucial events in the development of T cells, leading to a diverse yet non-autoreactive immune system. A breakdown in either of these processes could lead to either a reduced T cell repertoire or the escape into the periphery of autoreactive T cells - both clearly having deleterious consequences for the health of the individual. This review aims to summarise the current status of research in thymic positive selection with emphasis on the role of different cell types and peptides.

Animals↗
PubMed1997

Specific recognition of thymic self-peptides induces the positive selection of cytotoxic T lymphocytes.

To understand how thymic selection gives rise to T cells that are capable of major histocompatibility complex (MHC)-restricted recognition of antigen but are tolerant of self, we directly examined how peptide/MHC ligands expressed on thymic epithelial cells trigger the positive selection of immature thymocytes. We demonstrate that abundant self-peptides, purified from the H-2D(b) molecules of thymic epithelial cells, are specifically recognized during the positive selection of CD8+ T cells, implying that positive selection generates a repertoire of T cells that is weakly self-reactive. We also found that this recognition is somewhat cross-reactive, thereby providing an explanation for how the specific recognition of a limited repertoire of thymic self-peptides can select a diverse repertoire of T cells.

Animals↗
PubMed1995

Asymmetric signaling requirements for thymocyte commitment to the CD4+ versus CD8+ T cell lineages: a new perspective on thymic commitment and selection.

Differentiation of immature CD4+ CD8+ thymocytes into mature CD4+ CD8- and CD4-CD8+ T cells requires that synthesis of one or the other coreceptor molecule be terminated, a process referred to as lineage commitment. The present study has utilized a novel coreceptor reexpression assay to identify lineage commitment in immature thymocytes and has found that the MHC recognition requirements for CD4 commitment and CD8 commitment fundamentally differ from one another. Remarkably, we found that thymocyte commitment to the CD8+ lineage requires MHC class I-dependent instructional signals, whereas thymocyte commitment to the CD4+ lineage is MHC independent and may occur by default. In addition, an unanticipated relationship between lineage commitment and surface phenotype has been identified. These results are incompatible with current concepts and require a new perspective on lineage commitment and positive selection, which we refer to as asymmetric commitment.

Animals↗
PubMed1993

Adhesive interactions in thymic development: does selective expression of CD45 isoforms promote stage-specific microclustering in the assembly of functional adhesive complexes on differentiating T lineage lymphocytes?

CD45 isoform transitions appear to play essential roles in both life and death, and correlate with the stages of thymocyte development during which there is a change in physical location from medullary and/or outer cortical areas to the inner cortex. This work speculates that CD45 isoforms, through a focal role in the assembly of adhesive complexes mediated by the external domains, participate in the maintenance and/or modulation of migratory behaviour by differentiating thymocytes, or alternatively in the anchoring of thymocytes in a generative micro-environment. The objective of the sections that follow is to formulate the hypothesis that CD45 isoforms, through their differential interactions with adhesion molecules expressed by T cells, profoundly influence cell motility and consequent micro-environmental localization. An adhesive assembly of CD45 and adhesion molecules on the outside, and of the adhesive complex with the cytoskeleton on the inside, would promote CD45-mediated regulation of adhesion/de-adhesion through lateral external interactions mediated by external domains of CD45 isoforms, through enzymatic modulation of the cytoplasmic domains of adhesion molecules by the CD45 tyrosine phosphatase activity, and through phosphatase control of cytoskeletal assembly and disassembly.

Animals↗
PubMed2000

Normal thymic architecture and negative selection are associated with Aire expression, the gene defective in the autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

T cell development is tightly controlled by thymic stromal cells. Alterations in stromal architecture affect T cell maturation and the development of self-tolerance. The monogenic autoimmune syndrome APECED (autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy) is characterized by the loss of self-tolerance to multiple organs. Although mutations in the autoimmune regulator (AIRE) gene are responsible for this disease, the function of AIRE is not known. Here we report on the spatial and temporal pattern of murine Aire expression during thymic ontogeny and T cell selection. Early during development, thymic Aire transcription is critically dependent on RelB and occurs in epithelial cells in response to lymphocyte-mediated signals. In adult tissue, Aire expression is confined to the medulla and the corticomedullary junction, where it is modulated by thymocytes undergoing negative selection. Aire may determine thymic stromal organization and with it the induction of self-tolerance.

Animals↗
PubMed1996

Breaking self-tolerance in nonobese diabetic mice.

Unresponsiveness to self is maintained through two mechanisms of immune regulation: thymic-negative selection and peripheral tolerance. Although thymic-negative selection is a major mechanism to eliminate self-reactive T cells, normal mice have readily detectable populations of T cells reactive to self-proteins but do not exhibit autoimmune responses. It has been postulated that autoimmune disease results from breakdown or loss of peripheral tolerance. We present data that demonstrate that peripheral tolerance or unresponsiveness to self can be broken in nonobese diabetic (NOD) mice. Immunization of NOD mice (but not of conventional mice) with self-peptides caused an immune response to self-peptide with resultant autoproliferation of peripheral lymphocytes. Autoproliferation of self-reactive T cells in NOD mice resulted from the recognition and proliferation of the activated T cells to endogenously processed and presented self-antigens. This loss of self-tolerance demonstrated in vitro may well be the basis of NOD autoimmune disease in vivo.

Amino Acid Sequence↗
PubMed1997

CD8 T cells from major histocompatibility complex class II-deficient mice respond vigorously to class II molecules in a primary mixed lymphocyte reaction.

Mature CD4+ and CD8+ T cells are restricted by major histocompatibility complex (MHC) class II and class I molecules, respectively. In a primary mixed lymphocyte reaction (MLR), CD8+ T cells from C57BL/6 (B6) mice can respond to allo-class I molecules, but not allo-class II molecules. However, a significant fraction of CD8+ T cells from C57BL/6 class II-deficient (B6Aalpha-) mice violate this rule by responding vigorously in a MLR to class II molecules. The frequency of responding cells is approximately 50% of that of B6 CD8+ T cells responding to B6bm1 allo-class I molecules. This response requires neither appropriate co-receptor, i.e. CD4, nor exogenous lymphokines, indicating that interactions between the T cell receptors (TCR) and class II molecules are remarkably efficient. Since these CD8+ T cells are positively selected by class I molecules in the thymus of class II-deficient mice, these CD8+ T cells should interact with both classes of MHC molecules. The absence of thymic negative selection by class II molecules may result in the production of these CD8+ T cells. The data imply that a substantial fraction of CD4+CD8+ double-positive thymocytes in wild-type mice interacts with both classes of MHC molecules prior to thymic selection.

Animals↗
PubMed2001

UEA-I-binding to thymic medullary epithelial cells selectively reduces numbers of cortical TCRalphabeta+ thymocytes in FTOCs.

Thymic medullary epithelial cells (TMECs) constitute a major stromal cell type, the function of which is incompletely understood. Some TMECs express L-fucose-glycosylated proteins on their plasma membrane; these have been shown to specifically bind the lectin UEA-I. We exploited this observation to investigate the consequences of in situ blockage of TMECs in FTOCs by UEA-I. In UEA-I-treated FTOCs, we noted a decreased cellularity among TCRalphabeta+ but not TCRgammadelta+ cells. In fact, CD3- and CD3lo cortical cells were markedly depleted, while CD3hi cells were unaffected. Since the affected cell subsets are in a different compartment from that where UEA-I binding occurs, it is likely that the effect is mediated through a soluble factor. Two possible mechanisms are proposed: a reduced activation of either TMECs or of medullary thymocytes which normally bind to them, results in lowered production of soluble factors responsible for cortical thymocyte proliferation. Alternately, the binding of UEA-I to TMECs could activate the latter to produce signals inhibitory to cortical thymocytes.

Animals↗
PubMed1993

CD8 is needed for positive selection but differentially required for negative selection of T cells during thymic ontogeny.

During thymic development, immature thymocytes expressing major histocompatibility complex (MHC) class I-restricted T cell receptors (TcR) differentiate into CD8+ T cells with cytolytic functions. To evaluate the role of CD8 in positive and negative selection during thymic ontogeny, mice rendered CD8-null by gene targeting were bred with three lines of transgenic mice expressing unique MHC class I-restricted TcR. In all three instances CD8 was required for positive selection of MHC class I-restricted transgenic T cells. The efficiency of positive selection decreased in accordance with a reduced level of CD8 expression on thymocytes. Surprisingly, there was a differential requirement for CD8 expression in negative selection of MHC class I-restricted thymocytes, depending on the antigen specificity of TcR. These observations show that CD8 is essential for positive selection but is differentially required for negative selection of MHC class I-restricted T cells. Thus thymic selection, at least for negative selection, can occur in the absence of the CD8 accessory molecule.

Animals↗
PubMed1981

The human thymic environment.

Selected combinations of antisera labelled with different fluorochromes were used to explore the cellular interactions in the human thymic cortex and the medulla. In the early fetal thymus the cortical epithelial cells and an apparently more mobile medullary interdigitating cell population expressed large amounts of Ia-like (HLA-DR) and moderate amounts of HLA-A,B,C antigens while the lymphoid cells in the cortex expressed human T lymphocyte and cortical thymocyte antigens but were Ia-, HLA-A,B,C-. This arrangement is maintained in the infant thymus. The terminal deoxynucleotidyl transferase enzyme is first generated in cortical thymocytes (around the 17th week of gestation) and appears in bone marrow precursor cells later. In the infant thymus the lymphoid populations could be classified, according to their reactivity pattern with the new monoclonal antibodies of the OKT series, into three cell types: putative prothymocytes, typical cortical thymocytes and medullary thymocytes. Among the medullary population the majority showed the phenotype of the "inducer" cell and a minority showed that of "suppressor-cytotoxic" cells. The thymic medulla (and interdigitating cells in peripheral lymphoid organs) may predominantly contribute to the generation of "inducer" T lymphocytes.

Animals↗
PubMed2006

Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) is the most common cause of poor long-term outcomes after allogeneic bone marrow transplantation (BMT), but the pathophysiology of chronic GVHD still remains poorly understood. We tested the hypothesis that the impaired thymic negative selection of the recipients will permit the emergence of pathogenic T cells that cause chronic GVHD. Lethally irradiated C3H/HeN (H-2k) recipients were reconstituted with T-cell-depleted bone marrow cells from major histocompatibility complex [MHC] class II-deficient (H2-Ab1-/-) B6 (H-2b) mice. These mice developed diseases that showed all of the clinical and histopathological features of human chronic GVHD. Thymectomy prevented chronic GVHD, thus confirming the causal association of the thymus. CD4+ T cells isolated from chronic GVHD mice were primarily donor reactive, and adoptive transfer of CD4+ T cells generated in these mice caused chronic GVHD in C3H/HeN mice in the presence of B6-derived antigen-presenting cells. Our results demonstrate for the first time that T cells that escape from negative thymic selection could cause chronic GVHD after allogeneic BMT. These results also suggest that self-reactivity of donor T cells plays a role in this chronic GVHD, and improvement in the thymic function may have a potential to decrease chronic GVHD.

Adoptive Transfer↗
PubMed2001

Thymic development and repertoire selection: the rat perspective.

This review summarizes our current knowledge of T-cell maturation and repertoire selection in the rat thymus. Some unique features of early thymocyte development and of CD4/CD8 lineage decision are described. A detailed analysis of lineage progression through the CD4, CD8 "double positive" compartment and T-cell receptor-induced CD8 T-cell maturation in cell culture is provided. A second emphasis is placed on interactions between germline-encoded T-cell receptor elements with MHC molecules in thymic repertoire selection and alloreactivity

Animals↗
PubMed1983

Effects of in vivo Friend leukemia virus infection on levels of serum thymic factors and on selected T-cell functions in mice.

The levels of serum thymic factor(s) (STF), of Thy-1.2 positivity of splenocytes [as measured by their azathioprine (AZ) sensitivity], and of Thy-1.2-positive "spontaneous" spleen rosette-forming cells (SSRFCs), as well as the presence of infectious virus in the thymus, were assessed as a function of time after virus inoculation in susceptible DBA/2, partially resistant BALB/c, and fully resistant C57BL/6 mice given the polycythemia- or anemia-inducing strain of Friend leukemia virus (FLV-P and FLV-A, respectively). As early as Days 2 to 3, the levels of STF and of AZ sensitivity of splenocytes were profoundly decreased in DBA/2 mice, and, to a lesser extent, in BALB/c mice given FLV-P; however, SSRFCs/spleen were increased in both mouse strains. Conclusive evidence of infectious FLV-P was obtained in the thymuses of DBA/2 mice soon after infection. In mice of the same strains infected with FLV-A, STF levels were similarly decreased, but AZ sensitivity of splenocytes was unaffected, and SSRFCs were decreased. Evidence of early FLV-A infection in the thymus of DBA/2 mice was likewise obtained. In C57BL/6 mice given FLV-A, STF levels, AZ sensitivity of splenocytes, and SSRFC showed changes similar to, but of lower magnitude than, those in BALB/c mice. On the other hand, in C57BL/6 mice given FLV-P, the decrease in STF and AZ sensitivity was almost as pronounced as in susceptible DBA/2 mice in the face of complete absence of infectious virus or viral markers in the thymuses. The observed changes are ascribed to virus infection in view of the following: (a) good temporal correlation between these changes and virus infection; (b) absence of any change in mice given heat-inactivated viruses or spleen homogenate of normal DBA/2 mouse spleen; (c) overall good correlation between mouse genotype and genetic (Fv-1 and Fv-2) restrictions of virus infection on one hand and the magnitude of the observed changes on the other. In particular, the decrease in STF and SSRFC levels is ascribed to the replication-competent (Friend-murine leukemia virus) component of Friend leukemia virus complex, whereas the decrease in AZ sensitivity of splenocytes and the increase of SSRFCs are ascribed to the defective spleen focus-forming virus component of the complex. All changes described so far were transient, since they were not detectable beyond 42 days after virus inoculation in overtly leukemic animals. The observed derangements of thymus-derived immune functions may play an important cofactor role during the onset of leukemia in mice genetically permissive to Friend leukemia virus replication and transformation, but they do not seem relevant to the maintenance of leukemia.

Animals↗
PubMed1999

Thymic cysts in harbor porpoises (Phocoena phocoena) from the German North Sea, Baltic Sea, and waters of Greenland.

Thymic cysts have not been previously reported in harbor porpoises (Phocoena phocoena). Two hundred forty stranded or "by-caught" harbor porpoises originating from the German North Sea and Baltic Sea and 14 animals from the waters of Greenland were necropsied. Thymuses of 78 porpoises of the North Sea and Baltic Sea were considered suitable for histopathologic examination based on the extent of postmortem autolysis. Immunohistochemistry using an anti-cytokeratin antibody was employed to demonstrate thymic epithelial structures in selected cases. Thymic macrocysts were rare and were only found in animals > or =7 years of age. Thymic microcysts, lined by a single cytokeratin-positive cell layer, were common in involuting thymuses, and the prevalence increased with advancing age. Thymic cysts might have arisen from degenerating Hassall's corpuscles or condensed epithelial reticulum. Thymuses were easily identified macroscopically in most adult healthy harbor porpoises, suggesting that physiological thymic involution proceeds slowly in this species.

Animals↗