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PubMed2004

The fourth way? Harnessing aggressive tendencies in the thymus.

During late stages of thymic development, T cells must chose between different fates, dictated by their TCR specificity. Typically, this is thought of as a choice between three alternatives (being positive selection for useful T cells vs negative selection or neglect for harmful or useless T cells). However, there is growing evidence for a fourth alternative, in which T cells are positively selected by agonist ligands, which would normally be expected to induce T cell deletion. In this review, we will discuss where and when agonist selection is induced and whether this should be considered as a novel form of thymic selection or as an alternative differentiation state for Ag-exposed T cells.

Cell Differentiation↗
PubMed1995

Manipulation of the immune response by foreign gene expression in the thymus.

Retroviral gene transfer vectors have been developed for optimal in vivo gene therapy. Ideally, these vectors should target gene expression specifically to selected tissues or organs. Our studies focus on the development of retroviral vectors for gene delivery to the thymus. The goal of these studies is to utilize thymic expression of exogenous genes to manipulate the immune repertoire. We have characterized the selective thymic tropism of a molecular clone of Gross murine leukemia virus, GD-17, to thymic medullary epithelial cells using immunohistochemical staining and confocal microscopy. Specific expression of viral antigens in the thymus lead to the induction of immunologic tolerance to GMuLV proteins. This tissue specific vector may thus be used to study the requirements of epithelial mediated tolerance induction, and provide a more efficient tool for gene therapy.

Animals↗
PubMed1999

A classification based on T cell selection-related phenotypes identifies a subgroup of childhood T-ALL with favorable outcome in the COALL studies.

During T cell selection in the thymic cortex more than 90% of the thymocytes are eliminated by apoptosis. Based on this biology, we propose to define blasts of T cell acute lymphoblastic leukemia (ALL) with the phenotype of cortical thymocytes (CD1+ and/or CD4+ 8+) as selection-related (SR) and all other T-ALL immunophenotypes as non-selection-related (NSR). The COALL cooperative treatment studies for childhood ALL offer a tool to study the outcome in T-ALL subgroups as children with T-ALL are allocated uniformly to the high risk arm of the protocol. In the COALL-85, -89 and -92 protocols, 39/83 cases presented as SR and 44/83 cases as NSR. Five-year event-free survival of SR phenotype is significantly better compared to the NSR group (0.87 +/- 0.06 vs 0.66 +/- 0.07, log rank test, P = 0.01). T-ALL with SR phenotype is a distinct subgroup of leukemia with excellent prognosis under a high risk treatment protocol.

Adolescent↗
PubMed1990

Selection of CD4+CD8+ thymocytes by complex formation with medulla-derived epithelial cells.

The role of lymphostromal complexes in T-cell differentiation is far from elucidated, mainly because a clear association of a particular stromal cell type with a distinct thymocyte subset has never been identified. Using an in vitro system, detecting the adherence of thymocytes to a thymic medullary epithelial cell line (E-5), we showed that the phenotype of these thymocytes was that of cortical type: Thy-1hi, LFA-1+, PNAhi, CD4+CD8+, MEL-14-/lo, IL-2R-, CD3-/lo, and TcR V beta 8-/lo. They were enriched in cells in G2/M at the time of complex formation, showed a higher basal proliferation in culture, and did not respond to PHA, IL-2 and only marginally to Con A. These data show that complex formation with mouse thymic medullary epithelium selects for CD4+CD8+ thymocytes, as shown by the marked decrease in CD4+CD8-/CD4-CD8+ thymocytes, and the incapacity of CD4-CD8- thymocytes to adhere.

Animals↗
PubMed1994

Positive and negative selection of T cells in T-cell receptor transgenic mice expressing a bcl-2 transgene.

To explore the role of bcl-2 in T-cell development, a bcl-2 transgene was introduced into mice expressing a T-cell receptor (TCR) transgene encoding reactivity for the mouse male antigen HY presented by the H-2Db class I antigen of the major histocompatibility complex (MHC). Normal thymic development is contingent on the ability of immature thymocytes to interact with self-MHC molecules presented by thymic stroma (positive selection). Thus, thymocyte numbers are low in female anti-HY TCR transgenic mice with a nonselecting (H-2Dd) background. Expression of bcl-2 inhibited the death of nonselectable thymocytes since, strikingly, female H-2Dd bcl-2/TCR transgenic mice developed normal numbers of CD4+CD8+ thymocytes, although these did not mature further into functional T cells. Hence, TCR-MHC interaction may induce positive selection through two signals, one which saves cells from death by increasing Bcl-2 synthesis and another which promotes maturation. Male H-2Db anti-HY TCR transgenic mice normally have a very small thymus, due to deletion of the self-reactive T cells. Expression of bcl-2 reduced the efficiency of deletion, since bcl-2/TCR transgenic male mice accumulated 4- to 6-fold more thymocytes than did TCR transgenic male littermates. Anti-HY TCR-expressing cells were also more numerous in the peripheral lymphoid tissues, but these cells expressed abnormally low levels of CD8 co-receptor and were not responsive to the HY antigen. Thus, although bcl-2 expression hampers the deletion of immature self-reactive cells in the thymus, self-tolerance is maintained.

Animals↗
PubMed2002

The role of CD4 in regulating homeostasis of T helper cells.

Intrathymic T cell selection and peripheral activation of mature T cells are crucial for self-recognition and the general immune response to viral, bacterial, and tumor antigens. The T cell coreceptors, CD4 and CD8, contribute to the regulation of these processes. The importance of interactions between CD4 and molecules encoded by the class II major histocompatibility complex (MHC) for thymic T cell selection has been clearly established, however, the role of CD4-MHC class II interactions in T helper (TH) cell differentiation, in the maintenance of homeostasis in the peripheral immune system, and in the generation of memory TH cells is largely unclear. Here, we present evidence for a role of CD4 in controlling homeostasis in the peripheral immune system. We also demonstrate the importance of CD4-MHC class II interactions in inducing these previously not recognized functions of CD4.

Animals↗
PubMed2005

The timing of TCR alpha expression critically influences T cell development and selection.

Sequential rearrangement of the T cell receptor for antigen (TCR) beta and alpha chains is a hallmark of thymocyte development. This temporal control is lost in TCR transgenics because the alpha chain is expressed prematurely at the CD4- CD8- double negative (DN) stage. To test the importance of this, we expressed the HY alpha chain at the physiological CD4+ CD8+ double positive (DP) stage. The reduced DP and increased DN cellularity typically seen in TCR transgenics was not observed when the alpha chain was expressed at the appropriate stage. Surprisingly, antigen-driven selection events were also altered. In male mice, thymocyte deletion now occurred at the single positive or medullary stage. In addition, no expansion of CD8 alpha alpha intestinal intraepithelial lymphocytes (IELs) was observed, despite the fact that HY transgenics have been used to model IEL development. Collectively, these data establish the importance of proper timing of TCR expression in thymic development and selection and emphasize the need to use models that most accurately reflect the physiologic process.

Animals↗
PubMed1984

In vitro cultivation of nonlymphoid thymic cells: morphological and immunological characterization.

Nonlymphoid thymic elements play an important role in T-lymphocyte development, especially in the development of recognition of transplantation antigens (H-2 in the mouse). Understanding this process will require the isolation and characterization of these cells. A simple technique for the culture of an enriched population of murine thymic epithelium is described. The epithelial nature of these cells is evidenced by their morphology, electron microscopy, and keratin content. Readily distinguishable macrophages comprise a secondary population within these cultures. Antigens encoded in the I-A region of H-2 were found on 70% of thymic epithelial cells and H-2K on 30% of thymic epithelial cells. These antigens were generally present on distinct populations but doubly positive cells were observed. Thymic macrophages were found to have conventional receptors for the Fc fragment of immunoglobulin on their surface and could ingest antibody-coated sheep erythrocytes. Thymic epithelial cells did not have such Fc receptors. A striking observation was that thymic epithelial cells could bind and internalize autologous thymocytes. This selective thymocyte ingestion by thymic epithelium may have important implications in regard to processing of T-lymphocyte precursors.

Animals↗
PubMed1998

Double-positive thymocytes resistant to antigen-MHC-induced negative selection lack active caspase.

Thymocytes bearing autoreactive TCR are eliminated from the organism by a process termed negative selection. The molecular basis of this deletion has been recently shown to be a consequence of TCR-triggered activation of a caspase by certain peptide-MHC ligands in the immature CD4+CD8+ double-positive (DP) thymocyte subpopulation. Of note, the numerically minor TCRhigh DP thymocyte subpopulation, unlike the major TCRlow DP subset, is resistant to negative selection. Despite exposure to cognate peptide, TCRhigh DP thymocytes mature into single-positive thymocytes and are exported into the periphery. Here we investigated the mechanism by which these thymocytes escape negative selection. Using a cytochemical assay in conjunction with a caspase-specific affinity ligand, we demonstrate that the resistance of the TCRhigh DP thymocytes to negative selection correlates with the disappearance of TCR-triggered caspase activity in these cells. Thus thymocytes which have presumably begun the positive selection process inactivate the thymic caspase pathway and are no longer susceptible to negative selection.

Animals↗
PubMed1988

Alpha/beta T-cell antigen receptor gene and protein expression occurs at early stages of thymocyte differentiation.

Alterations in gene expression that orchestrate eukaryotic cellular differentiation often require appropriate interactions between differentiating cells and a specialized microenvironment. During T-lymphocyte differentiation, immature thymocytes undergo a stringent intrathymic selection process that requires intimate contact with thymic stromal elements. Since this selection process generates T cells that are self-tolerant and recognize nominal antigen only within the context of self-major histocompatibility antigen complex molecules, it is possible that thymocyte/stromal cell interactions are mediated, in part, by antigen-specific receptors expressed on differentiating thymocytes. However, the developmental stage at which alpha/beta antigen-specific receptors are expressed during T-cell maturation has been a matter of debate. To address this issue, we have studied alpha/beta T-cell antigen receptor gene and protein expression on normal thymocyte subsets of AKR/J mice, as well as on a panel of AKR/J primary thymic lymphomas characterized for CD4 (L3T4) and CD8 (Lyt-2) differentiation antigen expression. The data unequivocally demonstrate that alpha/beta heterodimers are expressed not only on phenotypically mature thymocytes but also on the majority of CD4+8+ double-positive cells that comprise the predominant nonmature thymocyte subset. Furthermore, a fraction of thymocytes in the CD4-8- double-negative compartment, known to contain progenitor cells, also expresses readily detectable cell-surface alpha/beta receptors. Therefore, during the process of intrathymic selection, interactions between nonmature thymocytes and stromal cells via the antigen-receptor complex may play a pivotal role in T-cell differentiation and should be considered in formulating schemes for functional T-cell selection.

Animals↗
PubMed1993

Development of alpha beta T cells.

Developing T cells in the thymus are subject to a screening process, through interactions with thymic stromal cells, from which T cells with appropriate T-cell receptors are selected. The recent generation of T-cell receptor transgenic mice and mice homozygous for disrupted T-cell receptor genes have now supplied tools that improve the prospect for a better understanding of the molecular mechanisms of this thymic selection process. In addition these model systems appear to indicate a role for a, not yet fully characterized, pre-T cell receptor complex in survival and further differentiation of pre-T cells.

Animals↗
PubMed1993

A novel cytokine-responsive cell surface glycoprotein defines a subset of medullary thymic epithelium in situ.

A hamster mAb (10.1.1), raised against long term cultures of uncloned thymic stromal cells, selectively labeled a subpopulation of medullary stromal cells in situ. By ultrastructural and phenotypic criteria, the stromal cells labeled by this mAb were judged to be epithelial. Although some of the 10.1.1+ epithelial cells were reticular, others were globular and some were associated with structures resembling Hassal's bodies. Ultrastructural immunohistochemistry suggested that 10.1.1 labeling of some of the epithelial cells was preferentially associated at areas of epithelial cell contact with adjacent thymocytes. Reactivity of thymic stromal cells with this antibody was developmentally regulated. A few scattered 10.1.1+ cells were observed at day 14 of gestation, and there were progressive increases in both the extent and intensity of 10.1.1 labeling evident through birth. One thymic stromal cell line, Z210.1, exhibited low levels of constitutive reactivity with this antibody. Exposure to IL-1 resulted in enhanced 10.1.1 reactivity of this cell line, with little, if any, additional response to TNF-alpha or IFN-gamma. Under the same conditions, ICAM-1 expression by this cell line was elevated in response to IL-1, TNF-alpha, or INF-gamma. Immunoprecipitation of detergent lysates prepared from Z210.1.7 cells exposed to IL-1 24 h before cell surface iodination identified a cell surface protein with a molecular mass of about 92 kDa under nonreducing conditions and about 95 kDa under reducing conditions. Digestion of 10.1.1 immunoprecipitates with N-glyconase resulted in a small (5 kDa) reduction in molecular mass. The molecule recognized by the 10.1.1 mAb was distinct from ICAM-1, which possessed a molecular mass of 100 kDa (nonreduced) and 110 kDa (reduced), and also displayed a smaller N-glyconase-resistant molecular mass (65 to 85 kDa).

Age Factors↗
PubMed2004

Could rheumatoid arthritis result from an abnormal T cell response towards lubricin/superficial zone protein?

The lack of some suppressor T cells (including TCD4+CD25+(high) positively selected first in thymic medulla) specific to a restricted set of autoantigens may be the common link between all patterns of rheumatoid arthritis. In other words, instead of a 'peak' of TCD4+ effector T cells common to all patients with rheumatoid arthritis (which has so far never been demonstrated), a 'hole' in TCD4+CD25+(high) responses towards a limited set of autoantigens responsible for the normal maintenance of tolerance within the joints may be shared by many patients with rheumatoid arthritis. The hallmark of this disorder is the involvement of tissues subjected to friction stress bathed in a lubricating fluid (rheumatoid nodules and bursae, tendinous sheaths, pleura, pericardium, sclera, and joints covered by hyaline cartilage). Consequently, autoantigens shared by all forementioned places may be better candidates than autoantigens restricted to the hyaline cartilage (like collagen II). Tenosynovitis, bursitis and rheumatoid nodules can herald rheumatoid arthritis, and rheumatoid pericarditis is very frequent at the histological level. Lubricin and superficial zone protein (SZP), which are closely related products of the megacaryocyte stimulating factor (MSF) gene, are among the best candidate autoantigens for such a positive selection of suppressor T cells. Lubricin is responsible for most of the lubricating properties of synovial fluid, and SZP (expressed by the superficial articular chondrocytes from diarthrodial cartilages and lining cells of synovial villi) also shares lubricating and cytoprotective properties. Moreover, the expression of lubricin is very probable in pericardium and pleura, and can be induced by friction stress. Although this mucinous glycoprotein may already share close similarities at the antigenic levels with mucins previously demonstrated in Hassall's corpuscles of the thymus, evidence for the ectopic expression of lubricin/SZP within normal human thymus may further support this hypothesis. The prenatal positive selection within the thymus of a functional pool of TCD4+CD25+(high) clones specific for most peripheral tissues is critical (at least in mice) for the quality of tolerance for the rest of the organism's lifespan. Therefore, a poor expression of lubricin/SZP early in life within the human thymus may also favour a lack of suppressor T cells specific to tissues bathed with synovial fluid, i.e. the onset of rheumatoid arthritis later on in life. As studies of human thymus long before the onset of rheumatoid arthritis are hampered for obvious reasons, studies of murine thymus could be a first step. In as much as the human counterpart of lubricin is expressed in the thymic medulla of mice, the generation of knocked-out mice for its expression within the thymus could be one of the best models to test the above hypothesis. The stimulation of TCD4+CD25+(high) clones specific for immunodominant epitopes from the joints/synovial fluid (belonging perhaps to lubricin or SZP) could help restore a normal balance between effector T cells and suppressor T cells in rheumatoid arthritis patients.

Animals↗
PubMedDate not supplied

T-cell avidity and tuning: the flexible connection between tolerance and autoimmunity.

Thymic T-cell selection mechanisms generate a cross-reactive, self-MHC restricted peripheral T-cell pool. Affinity and avidity are of profound influence on this selection and the generation of immunity. Autoreactive T cells can escape thymic deletion by lowering their avidity and retain this "tuned" state in the periphery. Upon activation, tuned T cells can cause autoimmunity, while immunotherapeutic strategies may be hampered by existing T-cell tolerance. The regulation of T-cell avidity and tuning therefore determines the balance between tolerance and autoimmunity and should be taken into account in the design of therapeutic strategies aimed at T-cell reactivity.

Animals↗
PubMed1996

Unopposed positive selection and autoreactivity in mice expressing class II MHC only on thymic cortex.

The normal development of T cells in the thymus requires both positive and negative selection. During positive selection, thymocytes mature only if their T-cell receptors react with some specificity to host major histocompatibility complex (MHC) and host peptides. During negative selection, thymocytes die if their T-cell receptors react with too high an affinity to the presenting cell, self MHC, and peptides to which they are exposed. These two processes are important for the development of the T-cell repertoire and the acquisition of self-tolerance, but their precise location and temporal relationship are not known. We have used the keratin 14 (K14) promoter to re-express a class II MHC antigen (I-Ab) in class II-negative mice. The transgenic I-A molecule is expressed only on thymic cortical epithelium; thymic medullary epithelium and bone-marrow-derived cells are I-A negative. CD4+ cells are positively selected in K14 mice, but clonal deletion does not ocur in K14 mice or in relB-negative mice, which lack a thymic medulla. The K14 CD4 cells are autoreactive, as they proliferate extensively to and specifically lyse I-Ab-positive target cells. These autoreactive cells make up 5% of the peripheral CD4 T cells, providing and estimate of the minimal frequency of positively selected cells that must subsequently undergo negative selection for self-tolerance to be preserved. Thus positive and negative selection occur in anatomically distinct sites.

Animals↗
PubMed1996

Thymic, gonadal, and endocrine relationships in gilts and boars administered porcine somatotropin.

We hypothesized that much of the positive effect of porcine somatotropin (pST) on the immune system would be offset by the pST/IGF stimulation of gonadal function and that there would be negative effects on thymic weight and function from increased androgens in males. Male and female hogs (78 boars, 90 gilts) representing three genetic lines (lean, obese, and crossbred meat type) received 0, 2, or 4 mg of recombinant pST/d via implant for 42 d. Blood samples were collected on 0, 7, 14, 28, and 42 d of the trial for changes in pST, IGF-I, IGF-II, thymosin beta 4, dehydroepiandrosterone/dehydroepiandrosterone sulfate (DHEA/DHEASO4), and testosterone concentrations. Thymic, splenic, gonadal, and adrenal weights were collected at slaughter (d 42). Thymic weights increased with dose of pST in both sexes (P < .01), but splenic weights were unaltered. Adrenal weights increased with dose of pST (P < .01), but gonadal weights showed no response to pST in either sex or any line. Overall, concentrations of pST, IGF, and thymosin beta 4 increased with dose of pST. Serum testosterone concentrations in boars declined with dose of pST in lean and obese lines, and DHEA/ DHEASO4 declined in all lines with pST treatment. Testicular testosterone concentrations were not different among lines or doses of pST, indicating no stimulatory effect of increased pST/IGF-I on Leydig cell function. Although pST and its effects through increased circulating IGF are thought to be overall stimulants of growth and protein accretion, the actions on the tissues of the immune system (thymus/spleen) and steroidogenic tissues (adrenal/gonadal) can be selective. Increases in thymic weights and thymosin beta 4 concentrations from pST treatment in boars were partially due to the pST-induced decline in circulatory androgens, and the responses found in this in vivo model do not support pST/IGF effects documented in in vitro systems on Leydig cell function.

Animals↗