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PubMed1994

The T cell receptor repertoire of CD4-8+ thymocytes is altered by overexpression of the BCL-2 protooncogene in the thymus.

The bcl-2 gene encodes an intracellular, membrane-associated protein that protects immature cortical thymocytes from a wide variety of apoptotic stimuli, including glucocorticoids, radiation, and anti-CD3 treatment. Since cortical thymocytes are the primary target cells for thymic positive and negative selection processes, and since these processes are associated with cell death, we evaluated the role of bcl-2 in T cell development in two ways. In the first approach, transgenic mice expressing high levels of Bcl-2 in cortical thymocytes were mated with H-Y T cell receptor (TCR) transgenic mice, the latter being a well-defined system for the study of positive and negative selection of T cells. We found that the bcl-2 transgene had a dramatic effect on positive selection. This was manifested by a greatly increased production of mature thymocytes that were highly skewed towards the CD4-8+ lineage. The change involving CD4-8+ thymocytes occurred not only in bcl-2 transgenic mice, but was also observed in H-Y TCR/bcl-2 doubly transgenic mice, regardless of whether the H-Y TCR was expressed in the selecting (H-2b) or nonselecting (H-2d) environments. Furthermore, a large proportion of CD4-8+ thymocytes produced in H-2b H-Y TCR/bcl-2 doubly transgenic female mice expressed endogenous TCR alpha chains rather than the transgenic TCR alpha chain. These observations are consistent with the model that high expression of Bcl-2 in cortical thymocytes overrides the normal apoptotic pathway. This then allows the selection of CD4-8+ thymocytes expressing TCRs that are otherwise nonselectable. However, the bcl-2 transgene did not protect CD4+8+ thymocytes expressing the male-specific TCR from deletion in male doubly transgenic mice. In the second approach, we determined the level of bcl-2 mRNA expression in populations of thymocytes defined by their CD4/CD8 phenotypes using quantitative reversed transcriptase PCR techniques. Our results indicate that bcl-2 mRNA was expressed at a high level in immature CD4-8- thymocytes and in mature CD4+8- thymocytes. There is a dramatic downregulation of bcl-2 mRNA in CD4+8+ thymocytes, particularly those expressing a low level of TCR. CD4+8+ thymocytes that upregulated their TCR, likely as a result of receiving positive selection signals, also upregulated bcl-2 mRNA. This observation suggests that rescue of immature thymocytes from the programmed cell death pathway by positive selection signals is accompanied by the upregulation of bcl-2 mRNA.

Animals↗
PubMed1994

Mechanisms of tolerance induction in major histocompatibility complex class II-restricted T cells specific for a blood-borne self-antigen.

Transgenic mice expressing a major histocompatibility complex class II-restricted T cell receptor with specificity for a natural self-antigen, the fifth component of complement, were generated to analyze the mechanism of tolerance induction to a blood-borne self-protein. In the absence of C5 protein thymocytes from T cell receptor transgenic mice develop into mature CD4 single positive cells which emigrate into the periphery and mount C5-specific T cell responses upon immunization with C5. In the presence of circulating C5 protein, CD4 single positive thymocytes do not develop. Negative selection occurs late in thymic ontogeny leaving the bulk of CD4+8+ thymocytes unaffected. This phenotype may be due to a delay in contact with self-antigen presentation which, under physiological conditions, is inefficient in the cortex of C5+ mice, and therefore does not affect most immature double positive thymocytes. In contrast, in vitro exposure to C5(-)-presenting dendritic cells or in vivo injection of C5 peptide results in deletion of double positive thymocytes. C5+ transgenic mice are tolerant in vivo, but contain T cells in spleen and lymph nodes that secrete interleukin 2 and interferon gamma in response to C5 activation in vitro. When crossed onto a Rag1-/- background to prevent endogenous T cell receptor rearrangements, these peripheral potentially autoreactive cells do not appear. This indicates that endogenous T cell receptor rearrangements possibly leading to the expression of two receptors might be a prerequisite for their survival and export into the periphery.

Animals↗
PubMed1996

Virus-induced autoimmune disease: transgenic approach to mimic insulin-dependent diabetes mellitus and other autoimmune diseases.

The technology of cloning viral genes and expressing them in vivo under cell-specific promoters allows to dissect the role of viruses, host self proteins, host genetics and immune responses in the complex etiology of autoimmune disease. Expression of a viral transgene, that is really a marker for a host "self" protein per se in beta cells of the islets of Langerhans, need not cause disease. In our model, expression of a viral gene was not associated with disease over the lifetime of the animal. However, when the host becomes infected with a virus encoding the same gene as the transgene or one closely related to it, a resultant immune response directed against the virus also recognizes the transgene leading to progressive T-cell-mediated response and destruction of the tissue expressing the viral ("self") gene, leading to autoimmune disease. This multifactorial process is influenced by whether the viral transgene is expressed in the thymus as well as in the disease-related cell or target tissue. Thymic expression influences negative selection of responder lymphocytes and thus delays the onset of the autoimmune disorder. Further, the MHC haplotype or other background genes of an individual undergoing autoimmune dysfunction play a role in the affinity of binding of the transgene products to the MHC molecule and influence the degree of negative selection that occurs, thereby influencing the vigor of the resulting immune response. The current ability to express host or viral genes in unique cell populations, and to make double- or triple-tg mice in which various cytokine genes or lymphocyte activation genes can be expressed along with the viral gene, offers a unique possibility for molecular dissection of autoimmunity. With the information on hand, approaches to the prevention and treatment of human autoimmune disease are likely to be uncovered. Finally, animal models are available in which the onset, progression and control of molecular mimicry can be evaluated. Future studies should define roles played by cytokines, bystander and immune-specific cross-reactivity to viruses and other microbes in several autoimmune diseases.

Animals↗
PubMed2006

ShcA mediates the dominant pathway to extracellular signal-regulated kinase activation during early thymic development.

During thymic development, the beta selection checkpoint is regulated by pre-T-cell receptor-initiated signals. Progression through this checkpoint is influenced by phosphorylation and activation of the serine/threonine kinases extracellular signal-regulated kinase 1 (ERK1) and ERK2, but the in vivo relevance of specific upstream players leading to ERK activation is not known. Here, using mice with a conditional loss of the shc1 gene or expressing mutants of ShcA, we demonstrate that the adapter protein ShcA is responsible for up to 70% of ERK activation in double-negative (DN) thymocytes in vivo and ex vivo. We also identify two specific tyrosines on ShcA that promote ERK phosphorylation in vivo, and mice expressing ShcA with mutations of these tyrosines show impaired DN thymocyte development. This work provides the first in vivo demonstration of the relative requirement of upstream adapters in controlling ERK activation during beta selection and suggests a dominant role for ShcA.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Keratinocyte growth factor preserves normal thymopoiesis and thymic microenvironment during experimental graft-versus-host disease.

Thymus-dependent reconstitution of the peripheral T-cell compartment is critical for the successful outcome of bone marrow transplantation. However, graft-versus-host disease (GVHD) affects thymic stromal function and thus prevents normal T-cell maturation and selection. To determine whether cytoprotection of thymic epithelial cells (TECs) by keratinocyte growth factor (KGF) averts GVHD-related injury to the thymus, a nonirradiated murine parent-->F(1) transplantation model was investigated. Administration of KGF between days -3 and +3 of GVHD induction preserved normal thymic size, cellularity, and thymocyte phenotype when measured 2 weeks after transplantation and compared with saline-treated parent-->F(1) mice that received allogeneic transplants. Moreover, the characteristic GVHD-induced impairment in cell cycle progression of pro- and pre-T cells was prevented by KGF. However, the normal phenotypic and functional status of the thymus did not correlate with the higher number of GVHD-inducing mature donor T cells in thymi of KGF-treated mice. Importantly, extensive analysis of the different TEC populations within the thymic cortex and medulla revealed an almost normal stromal architecture and composition in GVHD mice treated with KGF. These observations are likely to reflect an indirect effect of KGF on thymopoiesis as KGF-receptor expression was demonstrated to be restricted to TECs. Thus, pharmacologic doses of KGF appear to exert a potent effect on TEC function, which in turn allows for normal T lymphopoiesis to occur during acute GVHD.

Animals↗
PubMed2006

EphA receptors inhibit anti-CD3-induced apoptosis in thymocytes.

The EphA receptor tyrosine kinases interact with membrane-bound ligands of the ephrin-A subfamily. Interaction induces EphA receptor oligomerization, tyrosine phosphorylation, and, as a result, EphA receptor signaling. EphA receptors have been shown to regulate cell survival, migration, and cell-cell and cell-matrix interactions. However, their functions in lymphoid cells are only beginning to be described. We show in this study that functional EphA receptors are expressed by murine thymocytes, including CD4(+)CD8(+), CD4(+)CD8(-), and CD4(-)CD8(+) subpopulations. We demonstrate that activation of EphA receptors by the ephrin-A1 ligand inhibits the anti-CD3-induced apoptosis of CD4(+)CD8(+) double-positive thymocytes. Furthermore, ephrin-A1 costimulation suppresses up-regulation of both the IL-2R alpha-chain (CD25) and early activation Ag CD69 and can block IL-2 production by CD4(+) single-positive cells. In agreement, EphA receptor activation in thymocytes also inhibits TCR-induced activation of the Ras-MAPK pathway. Our findings suggest that EphA receptor activation is antithetical to TCR signaling in thymocytes, and that the level of engagement by ephrin-A proteins on thymic APCs regulates thymocyte selection.

Animals↗
PubMed1989

Traffic of mature lymphocytes into the mouse thymus.

The thymus is not generally considered to participate in bi-directional peripheral lymphocyte recirculation. We have demonstrated the entry of peripheral lymph node T cells using transfers between Thy-1 congenic mice. These peripheral T cells that enter the thymus bear an essentially medullary (or peripheral) phenotype and on section stains are confined to the medulla where they constitute 0.2-0.3% of the cells. These cells are remarkable for their frequent expression of the peripheral node homing receptor MEL-14 and for their persistence. Using transferred fluorescent labeled cells we also identify the entry of peripheral B cells into the thymus. Possible roles for peripheral B and T cells in the thymus include participation in thymocyte maturation or selection, the generation of thymic pathology and reactions to thymic pathologic processes.

Animals↗
PubMed1987

Human T cell gamma chain joining regions and T cell development.

We have cloned and sequenced two homologous J regions of the T cell gamma gene and localized one 5' of each constant region. They have been numbered J gamma 1.1 and J gamma 2.1; other J regions have been renamed in a similar manner. Southern blot analysis suggests that there is comparatively more rearrangement to these J regions in thymocytes than peripheral blood T cells. We propose that either there is gamma-chain gene rearrangement first to J gamma 1.1 or 2.1 and then to J gamma 1.3 or 2.3, or there is selected cell death of thymic T cells bearing a J gamma 1.1 or 2.1 rearrangement.

Adult↗
PubMed1993

Cyclosporin A-induced autoimmune disease in mice.

The immunosuppressive drug cyclosporin A (CsA) disrupts the process of thymic ontogeny and repertoire selection in the alpha beta T cell population. Although treatment with this agent does not cause overt abnormalities in adult animals by itself, in lethally irradiated rats reconstituted with syngeneic bone marrow cells, CsA treatment results in an autoimmune syndrome. In this report, a modified protocol is described to obtain a similar, but distinctive, pathologic syndrome in mice. The key elements of this protocol are stringent elimination of mature T cells from the bone marrow cells used to reconstitute the irradiated recipients and the use of high doses of CsA over a long course (6 wk) after irradiation. CsA treatment inhibits both the positive and negative selection of alpha beta thymocytes in normal young mice as well as in irradiated, T cell-deficient bone marrow-transplanted mice. An increased frequency of "forbidden" V beta 11 T cells is detected in these animals, but it is not clear that these cells are the actual initiators of the inflammatory lesions. In mice of several inbred strains treated by this protocol, striking inflammatory lesions develop in the colon, with less intense, but significant lesions in liver, stomach, and pancreas. Unlike allogeneic graft-vs-host disease, no lesions are found in the small intestine. Examination of these lesions by immunohistochemistry demonstrates that the lesions are composed primarily of T cells and macrophages, with focal aggregates of small B cells present. The same pattern of inflammatory lesions can be adoptively transferred with lymphoid cells from the CsA-treated animals at the peak of lesion development to irradiated syngeneic recipients. The transfer of active lesions is blocked by the co-transfer of normal syngeneic T cells to these recipients. Although similar to the previously described system in rats, these findings emphasize several novel features. In mice, we find an absolute requirement for the elimination of mature T cells from the bone marrow source to develop active inflammatory lesions. The particular tissues affected are also distinctive, especially the unusual feature of severe inflammation in the colon, but no involvement of the small intestine. The mechanism by which the presence of normal T cells suppresses the development of active autoimmunity in this model may have implications for the etiology of localized inflammatory lesions in general.

Animals↗
PubMed1993

Differential usage of T cell receptor V gene segments in CD4+ and CD8+ subsets of T lymphocytes in monozygotic twins.

The TCR confers immunity by the specific recognition of foreign Ag peptides in the context of self-MHC molecules. The mechanisms controlling TCR selection and repertoire generation are not clearly understood and seem to occur in an apparently random, (self) Ag-driven manner. To address the question to what extent the TCR repertoire is randomly shaped or genetically predetermined, we have analyzed the alpha beta TCR repertoire of the CD4+ and CD8+ subsets of peripheral blood lymphocyte cultures of monozygotic twins by using the polymerase chain reaction technique with TCR V region gene family-specific oligonucleotide primers. Our studies demonstrate that there is high concordance in the overall patterns of V gene usage within a pair of twins, particularly in V beta usage (mean V beta CD4+ R2 = 0.869 and CD8+ R2 = 0.833) and to a lesser extent V alpha usage (mean V alpha CD4+ R2 = 0.621 and CD8+ R2 = 0.627); whereas the patterns between unrelated individuals show more variability. This study has also demonstrated that the V alpha and V beta genes are not randomly used within the CD4+ and CD8+ subsets. We observed significant preferential skewing of several V alpha or V beta gene families to either the CD4+ or CD8+ subset in the majority of individuals analyzed (p-value range = 0.0476 to < 0.001). In particular, V alpha 11, 17, 22, and V beta 3, 9, 12, 18 were skewed to the CD4+ subset; whereas V alpha 2, 6, 12, 15, 20 and V beta 7, 14, 17 were skewed to the CD8+ subset. Furthermore, a number of the V genes showed patterns of skewing consistent only within a pair of twins. In three pairs of twins, V beta 2 was skewed to the CD4+ subset, whereas the fourth pair used almost equal frequencies of V beta 2 in both subsets. This observation was made for the V beta 2, 4, 5, 6, 8, 19 and V alpha 7, 16, 18, 21 families. Finally, the ratio of the relative V gene usage frequency that could be observed within an individual was conserved within the sets of twins; for instance, the relative amount of V beta 2 to that of V beta 3 was higher in both individuals of one set of twins, whereas it was lower in all of the other three sets. Together these observations suggest that the predominant influence shaping the TCR repertoire is genetically predetermined, of which, HLA-predicted selection mechanisms exerted during thymic maturation might be contributing factors.

Adult↗
PubMedDate not supplied

[Structure and function of the T-lymphocyte antigen receptor and its role in infectious diseases].

The T lymphocytes recognize antigens through antigen receptors (TcRs) and the major histocompatibility complex (MHC) molecules: they lysate the cells that bear the antigen, or release cytokines that are mediators of the immune response. The TcRs recognize antigens in the form of short peptides bound to MHC molecules. So far, there are two isotypes of TcR: gamma/delta and alpha/beta, which appear in the sequence during T-cell ontogeny. The process of selection of TcRs during thymic ontogeny obeys to molecular mechanisms which generate intracellular events that will participate in the gene expression of the TcR. The aim of the present paper is to review the molecular, structural, and functional aspects of the TcRs, and their role in human autoimmune infectious disease.

Animals↗
PubMed1996

[The in vitro induction of monocyte chemotactic protein-1 and interleukin-8 in whole human blood by low molecular weight thymus peptides].

Thymic peptides show immunoreconstitutive und tumor suppressive effects. They are used in oncology to improve the immunological status of patients. Chemokines are able to activate immune cells and inhibit tumor growth. In this study it was proved whether low molecular thymic peptides are able to increase the secretion of the chemokines monocyte chemotactic protein-1 (MCP-1), interleukin-8 (IL-8), macrophage inflammatory protein-1 alpha (MIP-1 alpha) and macrophage inflammatory protein-1 beta (MIP-1 beta) as well as the cytokine tumor necrosis factor-alpha (TNF-alpha) which is not related to chemokines using cell cultures of human whole blood. The thymic peptides induced a significant (p < 0.05) elevated secretion of MCP-1 and IL-8 whereas for MIP-1 alpha, MIP-1 beta and TNF-alpha no significant chances were seen. MCP-1 and IL-8 showed divergent dose-dependent effects and a different time kinetic of their secretion. The MCP-1 concentration correlated positively with the count of monocytes in whole blood of the volunteers while the IL-8 concentration in dependence with the incubation time correlated positively with the count of granulocytes or monocytes of the volunteers. The results indicate an activation of monocytes and/or granulocytes by low molecular thymic peptides followed by selective elevated secretion of MCP-1 and IL-8.

Adult↗
PubMed2006

A unified theory of central tolerance in the thymus.

Non-deletional tolerance resulting in the generation of regulatory T cells within the thymus is a key mechanism for the establishment of immunological self-tolerance. How the high-affinity self-reactive regulatory T cells escape negative selection and what type of antigen-presenting cells positively select them within the thymus are unsolved questions. Previous studies suggest that thymic epithelial cells are crucial for the positive selection of regulatory T cells in thymus. A recent study from my group shows that a subset of dendritic cells (that have been "educated" by the thymic stromal lymphopoietin molecule produced by a thymic cell type known as Hassall's corpuscles) positively select regulatory T cells within the medulla of human thymus. Here, I discuss the implications and historical context of this new result and suggest that a subset of mature dendritic cells within the thymic medulla protects the medium- to high-affinity self-reactive T cells from negative deletion and induces their differentiation into regulatory T cells in the thymus.

Animals↗
PubMed2002

The thymus and negative selection.

Maintenance of tolerance to self antigens is presumed to reflect a combination of central and peripheral tolerance. For T cells, central tolerance occurs during early T cell development in the thymus and causes cells with strong reactivity to self antigens to be destroyed in situ (negative selection). Here, we summarize evidence that negative selection can occur in the thymic medulla and affects a population of semimature HSA+ T cells. The influence of costimulatory molecules, Fas and cytokines on negative selection is discussed.

Animals↗
PubMed2005

Heterogeneity of thymic dendritic cells.

Thymus is the site of generation and selection of T-lymphocytes. It also contains phenotypically and functionally distinct dendritic cell (DC) populations, including conventional DC (cDC) and plasmacytoid DC (pDC). Thymic cDC are heterogeneous and contain two subsets: a major subset derived from the precursors within thymus, and a minor subset presumably of extrathymic origin. Increasing evidence suggest that thymic cDC can cross-present self-antigens to developing thymocytes and play an important role in thymocyte negative selection and central tolerance induction. Thymic pDC can produce type-I interferon upon appropriate activation. However, their role in a steady state thymus is currently unclear.

Animals↗
PubMed2001

A role for CD8 in limiting degeneracy of thymocyte selection.

The introduction of a soluble TCR (sTCR) recognizing class I major histocompatibility complex (MHC) in the fetal thymic microenvironment in vitro produces the selection of thymocytes with enhanced avidity for self class I MHC (8). The sTCR was supposed to impose enhanced avidity for self MHC at an early degenerate phase of TCR-driven selection. This could determine increased reactivity to self at later stages of differentiation when specificity of TCR-ligand interaction augments and the effect of sTCR vanishes. This hypothesis was based on the observed deletion of CD4+8+ thymocytes upon upregulation of TCR and the increase in cell size of some CD8+ cells which are expanded in long-term fetal thymus organ cultures (FTOC) as well as in the periphery of adoptively transferred nude mice. Here we show that the developing alphabeta thymocyte which does not express CD8 at the cell surface has a selective advantage in FTOC with sTCR, thus suggesting that participation of CD8 in self peptide/MHC recognition confers specificity to T-cell selection and results in excessive signaling in thymocytes in spite of the presence of sTCR.

Animals↗
PubMed2003

The influence of the thymic environment on the CD4-versus-CD8 T lineage decision.

T cell receptor signaling is an essential factor regulating thymocyte selection, but the function of the thymic environment in this process is not clear. In mice transgenic for major histocompatibility complex class II-restricted T cell receptors, every thymocyte is potentially selectable for maturation in the CD4 lineage. To address whether selection frequency affects positive selection, we created hematopoietic chimeras with mixtures of selectable and nonselectable precursors. With increased proportions of nonselectable thymocytes, positive selection of MHC class II-specific precursors was enhanced, generating not only CD4 but also CD8 thymocytes. These results indicate that the CD4 versus CD8 fate of selectable precursors can be influenced by the selection potential of its neighbors.

Animals↗
PubMedDate not supplied

Intrathymic inoculation of donor HLA class I-derived peptide generates donor-specific CD4+CD25+ regulatory T cells.

CD4(+)CD25(+) regulatory T cells are selected in the thymus to control autoreactive thymic escapees preventing autoimmunity that cannot be achieved by negative selection or deletion alone, thus playing an important role in the maintenance of immunological homeostasis. Not only significant in preventing autoimmunity, CD4(+)CD25(+) regulatory T cells have also been shown to be involved in allograft tolerance in organ transplantation. We have formerly introduced two lines of HLA class I transgenic mice to elucidate the role of HLA class I molecules in transplantation biology. Using a heterotopic cardiac transplantation model, we show herein that intrathymic inoculation of donor HLA class I-derived synthetic peptide results in the generation of CD4(+)CD25(+) regulatory T cells, which induce graft specific tolerance without any preconditioning of the recipient or use of immunosuppressive drugs. This study provides evidence of the novel therapeutic potential of CD4(+)CD25(+) regulatory T cells for clinical transplantation.

Amino Acid Sequence↗