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Results for “thymic selection”

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At least 199 records · Page 11Linked to original sources
PubMed1998

Engagement of CD99 induces up-regulation of TCR and MHC class I and II molecules on the surface of human thymocytes.

CD99 is a cell surface molecule involved in the aggregation of lymphocytes and apoptosis of immature cortical thymocytes. Despite its high level expression on immature cortical thymocytes, the functional roles of this molecule during thymic selection are only now being elucidated. Examination of the effects of CD99 engagement on the expression kinetics of the TCR and MHC class I and II molecules, which are involved primarily in thymic positive selection, revealed a marked up-regulation of these proteins on the surface of immature thymocytes. This increase was the result of accelerated mobilization of molecules stored in cytosolic compartments to the plasma membrane, rather than increased RNA and protein synthesis. Confocal microscopic analysis revealed the changes in subcellular distribution of these molecules. When CD99 was engaged, TCR and MHC class I and II molecules were concentrated at the plasma membrane, particularly at cell-cell contact sites. The TCRlow subpopulation of immature double positive thymocytes was much more responsive to CD99-mediated up-regulation than was the TCRhigh population. These findings suggest that CD99-dependent up-regulation may have possible implication in positive selection during thymocyte ontogeny.

12E7 Antigen↗
PubMed1990

The effects of MHC gene dosage and allelic variation on T cell receptor selection.

In a T cell receptor transgenic mouse model of thymic selection, the efficiency of selection of the transgenic alpha beta heterodimer is significantly enhanced in animals that express higher densities of the relevant major histocompatibility complex molecule (I-Ek/b). These results imply that there is a stochastic component to positive selection in the thymus. Allelic variants of the original selecting I-Ek molecule are either less efficient (E alpha k:E beta b) or incapable (E alpha k:E beta s and I-Ed) of mediating the selection of transgenic alpha beta + T cells. Two of these three I-E variants appear to differ from I-Ek in amino acid residues of the peptide binding site and not in residues capable of contacting the T cell receptor, suggesting that specific peptides, or conformations of peptides, play a role in positive selection. In contrast, mice transgenic for only the beta chain of this T cell receptor show selection for CD4+ T cells in the presence of all four I-E variants tested.

Alleles↗
PubMed1991

The role of polymorphic amino acids of the MHC molecule in the selection of the T cell repertoire.

Allelic variants of MHC molecules expressed on cells of the thymus affect the selection and the specificity of the T cell repertoire. The selection is based on either the direct recognition by the TCR of the MHC molecules, or the recognition of a complex determinant formed by self-peptides bound to MHC molecules. In an analysis of the T cell repertoire in bone marrow chimeras that express allelic forms of MHC class II molecules in the thymus epithelium, we find that amino acid substitutions that are predicted to affect peptide binding influence the selection of the T cell repertoire during thymic selection.

Amino Acids↗
PubMed1992

Negative selection of precursor thymocytes before their differentiation into CD4+CD8+ cells.

Thymic selection of the developing T cell repertoire is thought to occur at the CD4+CD8+ stage of differentiation and to be determined by the specificity of the T cell receptors (TCRs) that CD4+CD8+ thymocytes express. However, TCR signals can inhibit the differentiation of precursor thymocytes into CD4+CD8+ cells, which suggests that selection might occur earlier than thought. Indeed, in a negatively selecting male thymus, CD4-CD8lo precursor thymocytes that express a transgenic TCR to male antigen are developmentally arrested as a consequence of antigen encounter and fail to become CD4+CD8+. Thus, negative selection can occur before the CD4+CD8+ stage of differentiation.

Animals↗
PubMed2001

The shaping of the T cell repertoire.

By combining a TCRbeta transgene with a TCRalpha minilocus comprised of a single V and two J gene segments, we engineered a mouse line exhibiting ample but focused TCR diversity, restricted to CDR3alpha. Using single-cell PCR and high-throughput sequencing, we have exploited this system to scrutinize T cell repertoire selection and evolution. Some striking observations emerged: (1) thymic selection produces a repertoire that is very "bumpy," with marked overrepresentation of a subset of sequences; (2) MHC class I- and class II-restricted TCRs can be distinguished by minute, single-residue changes in CDR3alpha; and (3) homeostatic expansion and survival in the periphery can markedly remold the postselection repertoire, likely reflecting variability in the potential of cells displaying different TCRs to respond to homeostatic cues.

Animals↗
PubMed2007

Activation of CD4+ CD25+ regulatory T cell suppressor function by analogs of the selecting peptide.

CD4+ CD25+ Foxp3+ regulatory T (Treg) cells can undergo both thymic selection and peripheral expansion in response to self peptides that are agonists for their T cell receptors (TCR). However, the specificity by which these TCR must recognize peptide:MHC complexes to activate Treg cell function is not known. We show that CD4+ CD25+ Foxp3+ Treg cells can mediate suppression in response to peptides that are only weakly cross-reactive with the self peptide that induced their formation in vivo. Moreover, suppression could be efficiently activated by peptide analogs that were inefficient at inducing CD69 up-regulation, and that also induced little or no proliferation of naïve CD4+ CD25- Foxp3- T cells expressing the same TCR. These findings provide evidence that self peptide-specific CD4+ CD25+ Foxp3+ Treg cells can exert regulatory function in response to self- and/or pathogen-derived peptides with which they are only weakly cross-reactive.

Animals↗
PubMed2000

T-cell apoptosis and differential human leucocyte antigen class II expression in human thymus.

Relatively little is known of the details of human leucocyte antigen (HLA) expression and thymocyte selection in human thymus. In both humans and mice major histocompatibility complex (MHC) molecules have been described which show a highly restricted thymic expression. Such patterns may offer clues about cellular interactions in thymic selection because transgenic mice with MHC expression targeted to specific thymic sites show altered T-cell receptor (TCR) repertoire selection. We have analysed human thymic HLA class II expression, relating the expression pattern to sites of thymocyte apoptosis. While HLA-DQ is poorly expressed by most peripheral antigen-presenting cells (APC), thymus stains strongly for HLA-DQ as well as for HLA-DR. HLA-DM is abundant in medulla but weakly expressed by cortical cells. Class II expression in Hassall's corpuscles (HC) is unusual in several respects: we have previously shown them to be encircled by HLA-DO+ epithelial cells and here further demonstrate that HC are negative for HLA-DR and HLA-DP, but often positive for HLA-DQ and HLA-DM. Transcriptional control of HLA class II products at this site is thus unlike cells that have previously been studied. Apoptotic thymocytes are restricted to the cortex and the corticomedullary junction. However, a minority of apoptotic cells are visible in the medulla, these being found in the HLA-DQ positive HC. The apoptotic thymocytes in HC can be CD4+ single positive (SP), CD8+ SP or CD4+CD8+ double-positive (DP). This study thus shows that the HC within human thymic medulla are noteworthy both for their unusual hierarchy of HLA class II expression and because they are the only medullary site of thymocyte apoptosis. We propose that HC are a site at which mature thymocytes receive activation/tolerization signals from peptides reprocessed from apoptotic cells. The differential HLA transcriptional control at this site may indicate that specific T-cell subpopulations are affected.

Apoptosis↗
PubMed2006

Cutting edge: influence of the TCR Vbeta domain on the selection of semi-invariant NKT cells by endogenous ligands.

Invariant Valpha14 (Valpha14i) NKT cells are a murine CD1d-dependent regulatory T cell subset characterized by a Valpha14-Jalpha18 rearrangement and expression of mostly Vbeta8.2 and Vbeta7. Whereas the TCR Vbeta domain influences the binding avidity of the Valpha14i TCR for CD1d-alpha-galactosylceramide complexes, with Vbeta8.2 conferring higher avidity binding than Vbeta7, a possible impact of the TCR Vbeta domain on Valpha14i NKT cell selection by endogenous ligands has not been studied. In this study, we show that thymic selection of Vbeta7(+), but not Vbeta8.2(+), Valpha14i NKT cells is favored in situations where endogenous ligand concentration or TCRalpha-chain avidity are suboptimal. Furthermore, thymic Vbeta7(+) Valpha14i NKT cells were preferentially selected in vitro in response to CD1d-dependent presentation of endogenous ligands or exogenously added self ligand isoglobotrihexosylceramide. Collectively, our data demonstrate that the TCR Vbeta domain influences the selection of Valpha14i NKT cells by endogenous ligands, presumably because Vbeta7 confers higher avidity binding.

Animals↗
PubMed1995

CD40 ligand expression is developmentally regulated in human thymocytes.

Thymic selection involves the interaction between developing thymocytes and the thymic microenvironment. CD40 is expressed on thymic epithelial cells and on bone marrow-derived antigen-presenting cells in the thymus. We have investigated the capacity of human thymocytes to express CD40 ligand. CD40 ligand was not detectable on resting immature double-positive (CD4+/CD8+) or resting mature single-positive (CD4+/CD8- or CD4-/CD8+) thymocytes. Immature thymocytes failed to express CD40 ligand on their surface after stimulation with PMA and ionomycin, whereas stimulated CD4+/CD8- mature thymocytes expressed CD40 ligand. Northern blot analysis revealed that CD40 ligand mRNA was detectable in activated mature single-positive thymocytes. CD40 ligand expression by mature thymocytes was associated with the capacity to drive immunoglobulin isotype switching in purified B cells. These results demonstrate that the ability to express CD40 ligand is acquired late in thymocyte development and that mature thymocytes are capable of providing B cells with the activation signals necessary for immunoglobulin isotype switching.

Antigens, CD↗
PubMed2003

Thymic generation and selection of CD25+CD4+ regulatory T cells: implications of their broad repertoire and high self-reactivity for the maintenance of immunological self-tolerance.

Besides positive and negative selection of T cells, another function of the thymus in maintaining immunological self-tolerance is the production of CD25+CD4+ regulatory T cells capable of preventing autoimmune disease. They acquire the regulatory activity through the thymic selection process, and are released to the periphery as a functionally and phenotypically mature population. Our recent study with transgenic mice in which every class II MHC molecule covalently binds the same single peptide has revealed that a particular self-peptide/MHC ligand in the thymus can positively select a broad repertoire of functionally mature CD25+CD4+ regulatory T cells as well as naive T cells. Interestingly, the regulatory T cells bear higher reactivity than other T cells to the selecting ligand in the thymus even after negative selection by the ligand. This broad repertoire and high self-reactivity of CD25+CD4+ regulatory T cells, together with their high level expression of various accessory molecules, may guarantee their prompt and efficient activation upon encounter with a diverse range of self peptide/MHC complexes in the periphery, ensuring dominant control of self-reactive T cells.

Animals↗
PubMed1994

Thymic nurse cells are sites of thymocyte apoptosis.

Thymic stromal cells play important roles in thymocyte differentiation and selection. Thymic nurse cells (TNC) are thymic epithelial stromal cells that envelop two to 200 CD4+CD8+ thymocytes (TNC-T). The mechanism by which TNC complexes form and their role in thymocyte development are unknown. TNC have been implicated as specialized microenvironments for proliferation, positive selection, negative selection, and apoptosis. Using TCR-gamma junctional sequence analysis of thymocytes within individual TNC, eight of ten TNC analyzed were polyclonal, and two showed evidence of oligoclonality. TCR-alpha beta expression was not detectable on most TNC-T and SCID mice, which do not express TCRs because of a defect in TCR gene rearrangement, had normal numbers of thymocyte-bearing TNC. Thus, TCR expression is not necessary for TNC formation. Treatment of mice with Abs to CD3 epsilon, which induces apoptosis in immature thymocytes, resulted in an eightfold increase in TNC per thymus with 95.5% apoptotic TNC-T. These results suggest that a function of TNC is the clearance of nonfunctional, nonselected, apoptotic thymocytes.

Animals↗
PubMed1996

Monozygotic twins display differences in their allospecific cytotoxic T-cell repertoire.

The antigen-specific repertoire of peripheral blood T lymphocytes is generated by selection in the thymus followed by peripheral immunological events. While thymic selection is predominantly under genetic control, i.e. self-HLA molecules + self-peptides, confrontation with foreign antigens will lead to expansion of given T-cells, thus modifying the T-cell repertoire. To evaluate the relative importance of such modifying events the precursor frequencies (pf) of cytotoxic T lymphocytes (CTL) against given allogeneic HLA molecules were compared in six pairs of monozygotic twins. Using limiting dilution analyses, experiments with several different allogeneic stimulator/target cell donors were performed for each twin pair. In 12 out of 17 experiments, when the twins were tested against the same stimulator/ target cell donor, the CTL pf differed and the 95% confidence intervals were non-overlapping. This suggests that modifying effects by confrontation with foreign antigens play an important role in shaping the allospecific T-cell repertoire.

Adult↗
PubMed1994

Regulation of RAG-1 and CD69 expression in the thymus during positive and negative selection.

Successful interaction of the T cell receptor (TCR) with major histocompatibility complex (MHC) molecules during thymic selection down-regulates the expression of the recombination activating genes (RAG)-1 and -2 in cortical thymocytes and thereby prevents further endogenous TCR alpha-chain gene rearrangements (Borgulya, P., Kishi, H., Uematsu, Y. and von Boehmer, H., Cell. 1992. 69: 529-537; Brändle, D., Müller, C., Rülicke, T., Hengartner, H. and Pircher, H., Proc. Natl. Acad. Sci. USA 1992. 89: 9529-9533). To address the question whether down-regulation of RAG-1 activity represents an irreversible process we have blocked TCR-MHC interactions of thymocytes with thymic stromal cells. Firstly, transgenic (Tg) mice expressing a virus-specific MHC class I (H-2Db)-restricted TCR were injected with anti-Db or anti-CD8 monoclonal antibodies and RAG-1 expression was examined by in situ hybridization on thymus sections. The results show that cortical thymocytes up-regulated RAG-1 expression within 24 h after antibody administration. Secondly, immature thymocytes from TCR Tg mice were released from the thymic microenvironment and cultured in vitro for 14 h in single-cell suspension. The amount of RAG-1 mRNA was increased sixfold in cultured cells when compared to freshly isolated thymocytes. In addition, we show that immature thymocytes from TCR transgenic mice bearing non-selective MHC molecules (H-2d) down-regulated RAG-1 expression after antigen-induced TCR engagement. Cytofluorometric analysis further revealed that surface expression of CD69 on immature thymocytes inversely correlated with RAG-1 expression during positive and negative selection processes.

Animals↗
PubMed1994

Quantitative analysis of the efficiency of clonal deletion in the thymus.

One of the major mechanisms for establishing self-tolerance is the clonal deletion of self-reactive T cells during their development in the thymus. Using a TCR transgenic mouse model, we have established a quantitative ex vivo assay for examining the sensitivity and specificity of negative selection. Thymic organ cultures established from mice of varying MHC haplotypes were incubated with antigen, and the efficiency of clonal deletion assessed. We show here that clonal deletion of CD4+8+ thymocytes is sensitive to both the gene dosage and the allelic variation of MHC class II molecules expressed on thymic antigen-presenting cells. We also find that when epithelial cells in the thymic cortex are the only antigen-presenting cells expressing the appropriate MHC class II molecules, negative selection of CD4+8+ cells is as efficient as when antigen is presented on all thymic antigen-presenting cells. These studies demonstrate that the induction of self-tolerance via clonal deletion in the thymus is a function not only of antigen concentration, but also of MHC class II cell-surface density. In addition, together with the reports of others, these results confirm that cortical epithelial cells can mediate negative selection, and demonstrate that they do so in the intact thymic microenvironment.

Animals↗
PubMed1996

Human thymic epithelial cells express functional HLA-DP molecules.

HLA-DP molecules function as restriction elements in the presentation of foreign antigens to T cells by antigen presenting cells and certain HLA-DP molecules confer susceptibility to autoimmune disease. Because HLA molecules play an essential role in thymic selection and elimination of autoreactive T lymphocytes, we examined whether human thymic epithelial cells (TEC) expressed HLA-DP molecules. We present evidence that TEC obtained from short time culture express low but significant levels of HLA-DP molecules. The expression of HLA-DP molecules was comparable to or higher than the expression of HLA-DQ but lower than that of HLA-DR. Upon IFN-gamma treatment, HLA-DP expression was strongly upregulated. Since HLA-DQ and DR expression was upregulated in parallel, the hierarchy between MHC class II isotypes remained unchanged following interferon treatment. TEC elicited significant proliferation of HLA-DP allospecific primed lymphocyte typing (PLT) CD4 T cell lines. IFN-gamma treatment strongly upregulated the HLA-DP allospecific PLT responses whereas other PLT responses remained largely unchanged. In conclusion, these data indicate that human thymus epithelial cells express significant levels of functional HLA-DP molecules.

Child, Preschool↗
PubMed1989

Intrathymic signalling in immature CD4+CD8+ thymocytes results in tyrosine phosphorylation of the T-cell receptor zeta chain.

Thymic selection of the developing T-cell repertoire occurs in immature CD4+CD8+ double-positive thymocytes and is thought to be mediated by signals transduced by T-cell antigen receptor (TCR) molecules and possibly by CD4 and CD8 accessory molecules as well. It is not known, however, which signal-transduction mechanisms function in immature CD4+CD8+ thymocytes on engagement of TCR, CD4 or CD8 molecules. In mature T cells, CD4 and CD8 molecules are each associated with the src-like protein tyrosine kinase p56 lck and signals transduced by TCR and CD4 activate tyrosine kinases that phosphorylate TCR-zeta chains and other intracellular substrates. Consequently, we examined whether tyrosine kinases could be similarly activated in immature CD4+CD8+ thymocytes. Unexpectedly, we found that TCR-zeta chains from CD4+CD8+ thymocytes were already phosphorylated in vivo, and that dephosphorylation of this TCR subunit occurred on removal of CD4+CD8+ cells from their intrathymic environment. Rephosphorylation of TCR-zeta in cultured CD4+CD8+ thymocytes occurred rapidly in vitro, either in response to cross-linking of TCR, CD4 or CD8 by specific monoclonal antibodies, or on cell-cell contact. These observations indicate that tyrosine kinases are activated in vivo in immature CD4+CD8+ thymocytes undergoing thymic differentiation and selection. They also indicate that TCR, CD4 and CD8 molecules can function in CD4+CD8+ thymocytes as signalling molecules to activate tyrosine kinases and that phosphorylated TCR-zeta serves as a marker of these signalling events.

Animals↗
PubMed2003

Rapid induction of medullary thymocyte phenotypic maturation and egress inhibition by nanomolar sphingosine 1-phosphate receptor agonist.

Only a small number of T cells generated in the thymus each day are selected to replenish the peripheral T cell pool. Much is known about thymic selection; however, little is known of the mechanisms regulating medullary maturation and the release of mature T cells into the blood. Here we demonstrate a rapid acceleration of medullary thymocyte phenotypic maturation through loss of CD69 induced by sphingosine 1-phosphate (S1P) receptor agonist. Low nanomolar agonist concentrations selectively induce changes in CD69(int) CD62L(high) single positive T cells, resulting in down-modulation of CD69 within 2 h. While CD69 loss is accelerated, egress of mature T cells into blood is inhibited >95% within 2 h. Both processes exhibit parallel sensitivities and dose-responses. Together, these data reveal a potent means for rapidly regulating thymic export where S1P receptor agonism alters both phenotypic maturation and egress of thymocytes into blood during late thymic maturation. The S1P system is now shown to acutely regulate both thymic and lymph node egress. Inhibition of lymphocyte egress from thymus and lymph node can contribute synergistically to clinically useful immunosupression by disrupting recirculation of peripheral T cells.

Animals↗
PubMed1993

Immune discrimination of self and nonself: a unified theory for the induction of self tolerance among thymocytes and mature peripheral T cells.

A comprehensive model of immunological self tolerance is described which is based on the unique tenet that interactions between T cell antigen receptors (TcR) and specific MHC ligands may vary in efficacy (the ability of an MHC ligand to catalyze TcR-mediated activation). Based on this postulate, two interrelated mechanisms are described to explain how self tolerance is induced among immature thymocytes and mature peripheral T cells, respectively. In the thymus, APC apparently present a diverse array of self MHC ligands (complexes of self peptides and MHC glycoproteins) to clonotypic T cells. According to the first mechanism, immature thymocytes that efficaciously bind specific MHC ligands undergo TcR-mediated activation and programmed cell death whereas those that nonefficaciously bind MHC ligands are not activated and thereby escape negative selection. The latter T cells undergo positive selection and eventually constitute the mature T cell repertoire. This model of thymic selection ensures that interactions of mature T cells with self in peripheral tissues are predominantly nonefficacious. According to the second mechanism, clonotypically diverse T cells and individual APC comprise an integrative unit that measures antigenic complexity of the local environment as a basis to enable or disable immunogenic responses by mature T cells. T cells recognize efficacious MHC ligands (E) via the TcR/CD3 complex but are also able to detect nonefficacious MHC ligands (N) by conserved signal transduction pathways that are initiated upon cell-cell contact with APC. Clonotypic T cells relay E or N signals by conserved feedback pathways back to APC. APC integrate and compare large numbers of E or N signals to derive an E/N ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗