Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “thymic selection”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 163 records · Page 9Linked to original sources
PubMed2000

A NK1.1+ thymocyte-derived TCR beta-chain transgene promotes positive selection of thymic NK1.1+ alpha beta T cells.

As a consequence of the peptide specificity of intrathymic positive selection, mice transgenic for a rearranged TCR beta-chain derived from conventional alphabeta T lymphocytes frequently carry mature T cells with significant skewing in the repertoire of the companion alpha-chain. To assess the generality of such an influence, we generated transgenic (Tg) mice expressing a beta-chain derived from nonclassical, NK1.1+ alphabeta T cells, the thymus-derived, CD1. 1-specific DN32H6 T cell hybridoma. Results of the sequence analysis of genomic DNA from developing DN32H6 beta Tg thymocytes revealed that the frequency of the parental alpha-chain sequence, in this instance the Valpha14-Jalpha281 canonical alpha-chain, is specifically and in a CD1.1-dependent manner, increased in the postselection thymocyte population. In accordance, we found phenotypic and functional evidence for an increased frequency of thymic, but interestingly not peripheral, NK1.1+ alphabeta T cells in DN32H6 beta Tg mice, possibly indicating a thymic determinant-dependent maintenance. Thus, in vivo expression of the rearranged TCR beta-chain from a thymus-derived NK1.1+ Valpha14+ T cell hybridoma promotes positive selection of thymic NK1.1+ alphabeta T cells. These observations indicate that the strong influence of productive beta-chain rearrangements on the TCR sequence and specificity of developing thymocytes, which operates through positive selection on self-determinants, applies to both classical and nonclassical alphabeta T cells and therefore represents a general phenomenon in intrathymic alphabeta T lymphocyte development.

Animals↗
PubMed1992

Differentiation of an immature T cell line: a model of thymic positive selection.

Thymocyte differentiation is dependent upon recognition of major histocompatibility complex (MHC) molecules on thymic stroma, a process called positive selection. Here we describe an immature CD4+8+ T cell line derived from a TCR transgenic mouse that differentiates into CD4+8- cells in response to antigen and nonthymic antigen-presenting cells. When injected intrathymically, these cells differentiate in the absence of antigen. The ability of immature T cells to recognize MHC molecules in the absence of foreign antigen in the thymus can thus be attributed to a unique property of thymic antigen-presenting cells. These studies also demonstrate the phenotypic and functional changes associated with TCR-mediated T cell maturation and establish an in vitro model system of positive selection.

Animals↗
PubMed1977

Thymic microenvironment: selective activities of soluble and insoluble components.

Two components of the thymic microenvironment have been separated, and their biological properties have been studied. The first component, soluble thymic factor (STF), after injection into syngeneic recipients, provoked a temporary decrease in thymic weight on day 7, concomitant with an increase in the level of T cells in lymph nodes (but not in the spleen), followed by a general hypertrophy of lymph nodes peaking on day 21. In contrast, after the injection of the second component, insoluble thymic fraction (ITF), there was an increase in the number of prothymocytes in the thymic subcapsulary cortex, followed by general thymic hypertrophy on days 14 and 21. STF is believed to trigger a selective migration of lymph-node-seeking T cells from the thymus, whereas ITF seems to play a role in the differentiation step preceding that imparted by STF.

Animals↗
PubMed1999

A role for E2F1 in the induction of ARF, p53, and apoptosis during thymic negative selection.

E2F transcriptional activity controls the expression of many of the genes required for G1 to S phase progression. E2F1, one member of the E2F family, plays an important role in the induction of apoptosis. We have examined the role of the E2F1 transcription factor in apoptosis during T-cell maturation in the thymus. We show that E2F1 is required for the apoptosis of autoimmune immature T cells during thymic negative selection in vivo. This T-cell receptor-mediated apoptosis coincides with the E2F1-dependent increase of p19-ARF mRNA and p53 protein levels. In contrast, E2F1 is not required for the induction of apoptosis by glucocorticoids or DNA damage. These results demonstrate a specific role for E2F1, which triggers a pathway leading to ARF and p53 induction, in a physiological apoptosis pathway that is uncoupled from a normal proliferative event.

Animals↗
PubMed2000

On the role of high- and low-abundance class II MHC-peptide complexes in the thymic positive selection of CD4(+) T cells.

The role of self-peptides bound to MHC molecules in the selection of T cells in the thymus remains controversial. Here, we have tested whether a high-abundance single class II MHC-peptide complex has a dominant effect on the repertoire of CD4(+) T cells selected by low-abundance class II MHC-peptide complexes. For these studies, we have used H-2(b) mice that lack an invariant chain (Ii) (A(b)Ii(-)) and their transgenic variant (A(b)A(b)EpIi(-)) that co-expresses A(b) molecules covalently bound with a single peptide Ep(52-68). In these latter mice, close to 50% of all A(b) molecules are occupied by Ep(52-68) peptide. Although the A(b)Ep complex was abundantly expressed in the thymus under conditions excluding negative selection on bone marrow-derived cells, no striking quantitative difference between repertoires of TCR expressed on CD4(+) T cells in A(b)Ii(-) and A(b)A(b)EpIi(-) mice was noticed. Our results are consistent with the view that diverse, low-abundance self-peptides play an important role in thymic positive selection and do not support the notion that dominant, high-abundance peptides may be critical for shaping the TCR repertoire.

Amino Acid Sequence↗
PubMed1998

The role of peptides in thymic positive selection of class II major histocompatibility complex-restricted T cells.

A thymic epithelial cell line transfected with I-Ek was used in reaggregate cultures to study the role of peptides in positive selection of T cell receptor transgenic thymocytes. In this system, positive selection of CD4 SP cells occurred only after the addition of exogenous peptide. Analysis of antigen analogs indicated an inverse relationship between the antigenicity for peripheral T cells and the concentration of peptide required for positive selection. These data are most consistent with an avidity (rather than an affinity) model of positive selection, in which ligand density and the affinity of T cell receptor act in concert to determine the fate of developing thymocytes.

Amino Acid Sequence↗
PubMed1994

Targeted disruption within the CD3 zeta/eta/phi/Oct-1 locus in mouse.

To elucidate the role of the CD3 eta subunit of the T cell receptor (TCR) in thymic development, a CD3 eta -/- mouse was generated by gene targeting. Insertion of a neomycin resistance gene into exon 9 of the CD3 zeta/eta/phi locus disrupted expression of CD3 eta and CD3 phi without affecting the expression of CD3 zeta. Little difference was observed between wild type and CD3 eta -/- mice with regard to cellularity or subset composition in thymus and peripheral lymphoid organs. Furthermore, neither alloproliferative responses nor cytotoxic T lymphocyte generation and effector function was affected by the mutation. The effect of the CD3 eta -/- mutation on thymic selection was examined by crossing the CD3 eta knockout animals with anti-HY TCR transgenic animals: the absence of the CD3 eta subunit altered neither positive nor negative selection. Thus, CD3 eta is not required for thymic selection. Of note, the birth rate of the CD3 eta -/- animals was significantly lower than that of wild type or heterozygous animals (P = 0.041-0.002). This unexpected result is probably the consequence of an alteration in mRNA expression of the Oct-1 nuclear transcription factor in CD3 eta -/- animals. The CD3 zeta/eta/phi locus partially overlaps the gene encoding Oct-1 whose transcription is dysregulated by the CD3 eta -/- mutation. Our results clearly underscore the value of characterizing all products of a genetic locus disrupted by gene targeting.

Alleles↗
PubMed1997

Identification of a naturally occurring ligand for thymic positive selection.

In the thymus, positive and negative selection shape the T cell repertoire. It has previously been shown that positive selection, like negative selection, is the result of the interaction of the TCR with self-peptides bound to MHC. However, little is known about the number or nature of the self-peptide ligands that mediate positive selection in vivo. We devised a novel assay with enhanced sensitivity for low affinity TCR ligands to identify self-peptides that may be biologically relevant. At least eight K(b)-bound self-peptides were detected by this assay using thymocytes bearing the OT-I TCR (specific for OVAp/K(b)). The sequence of one of these peptides was determined using the recently developed technique of membrane preconcentration-capillary electrophoresis-tandem mass spectrometry. This peptide, CP alpha1, has limited sequence similarity to OVAp, yet was found to induce positive selection of OT-I thymocytes in fetal thymic organ culture.

Actin Depolymerizing Factors↗
PubMed2000

A motif in the alphabeta T-cell receptor controls positive selection by modulating ERK activity.

Positive selection allows thymocytes that recognize an individual's own major histocompatibility complex (self-MHC) molecules to survive and differentiate, whereas negative selection removes overtly self-reactive thymocytes. Although both forms of thymic selection are mediated by the alphabeta T-cell receptor (TCR) and require self-MHC recognition, an important question is whether they are controlled by distinct signalling cascades. We have shown that mutation of an essential motif within the TCR alpha-chain-connecting peptide domain (alpha-CPM) profoundly affects positive but not negative selection. Using transgenic mice expressing a mutant alpha-CPM TCR we examined the contribution of several mitogen-activated protein kinase (MAPK) cascades to thymic selection. Here we show that in thymocytes expressing a mutant alpha-CPM receptor, a positively selecting peptide failed to activate the extracellular signal-regulated kinase (ERK), although other MAPK cascades were induced normally. The defect in ERK activation was associated with impaired recruitment of the activated tyrosine kinases Lck and ZAP-70, phosphorylated forms of the TCR component CD3zeta and the adaptor protein LAT to detergent-insoluble glycolipid-enriched microdomains (DIGs). Therefore, an intact DIG-associated signalosome is essential for sustained ERK activation, which leads to positive selection.

Amino Acid Motifs↗
PubMed1996

Positive selection by thymic nurse cells requires IL-1 beta and is associated with an increased Bcl-2 expression.

A temperature-sensitive line of thymic nurse cells (tsTNC-1) that maintains the ability to selectively internalize immature alpha beta TCRloCD4+CD8+ thymocytes in vitro was used in long-term coincubation experiments to determine nurse cell function during the process of MHC restriction. The thymocyte subset released from its association with TNCs contained both viable and apoptotic cells. The cells that remained within intracytoplasmic vacuoles died through the process of programmed cell death. Surviving or rescued thymocytes in the released population displayed an increase in Bcl-2 protein expression. The rescue activity of TNCs was drastically reduced with the addition of antibodies against either class I or class II MHC antigens to cocultures. A subset of the TNC-rescued population matured from the alpha beta TCRloCD69- phenotype to alpha beta TCRhiCD(69+)-expressing cells only when IL-1 beta was added to cocultures. These results suggest that TNC rescue of early double-positive thymocytes from apoptosis is associated with an interaction between the TCR and the MHC and the onset of Bcl-2 expression. Maturation of thymocytes within the TNC-rescued population requires the costimulatory effects of IL-1 beta.

Animals↗
PubMed1991

Peripheral selection of the T cell repertoire.

T lymphocytes undergo selection events not only in the thymus, but also after they leave the thymus and reside in the periphery. Peripheral selection was found to be dependent on T cell receptor (TCR)-ligand interactions but to differ from thymic selection with regard to specificity and mechanism. Unlike thymic selection, peripheral selection required binding of antigen to the TCR, and it induced expansion of T cell clones. Tolerance to self antigens that are restricted to the periphery occurred through the elimination of self-reactive T cells and by the clonal anergy, which was associated with down-regulation of the alpha beta TCR and CD8.

Animals↗
PubMed1995

T cell development in CD8-/- mice. Thymic positive selection is biased toward the helper phenotype.

The CD4 and CD8 molecules are involved in T cell differentiation and activation. Nevertheless, efficient thymic maturation of helper T cells has been shown in the absence of the CD4 molecule. These CD4-deficient helper T cells expressed alpha beta-TCR and were able to control Leishmania infections and to mediate Ab class switch. Using mice deficient for the CD8 alpha-chain, we investigated whether a similar cytotoxic T cell population was generated in the absence of the CD8 coreceptor. A CD8-deficient cytotoxic T cell population corresponding to the described CD4-deficient helper T cell population was virtually absent both functionally and physically. These results support the idea that thymic maturation is asymmetrical and strongly biased toward the helper phenotype.

Animals↗
PubMed1989

HLA class II polymorphism: implications for genetic susceptibility to autoimmune disease.

Our understanding of HLA class II polymorphism has undergone a rapid evolution in the last few years. As in so many areas of modern biology, this progress has depended largely on the application of recombinant DNA techniques to the study of this gene family. In particular, the recent development of methods of gene amplification by means of the polymerase chain reaction has allowed for the rapid assessment of polymorphism in the human population. In addition, the elucidation by x-ray crystallographic analysis of the three-dimensional structure of an HLA molecule has been a major step. These areas of progress have now begun to converge to allow a more detailed approach to the problem of class II polymorphism and disease susceptibility. As discussed in this review, the data so far indicate that a few amino acid substitutions in class II molecules may exert a critical influence on susceptibility to autoimmune diseases such as RA and IDDM. The mechanism by which these class II polymorphisms predispose to autoimmune disease is still unknown. It is tempting to speculate that differences in the binding affinity of HLA molecules for autoantigens might be involved; however, as yet no specific autoantigen has been identified for either RA or IDDM. Intriguingly, sequence similarities have been observed between some viral proteins and class II molecules, raising the possibility that these infectious agents might induce autoimmunity by "molecular mimicry." Examples include the human cytomegalovirus protein, IE2 as well as the Epstein Barr virus gp110 protein. Other possible mechanisms involve more complex immunoregulatory effects, such as the absence of suppressor functions that appear to be under the influence of the HLA genes. To some extent, the persistent ignorance about the cause of autoimmunity reflects a general lack of knowledge concerning exactly how HLA polymorphisms exert immunoregulatory effects. For example, in addition to influencing antigen presentation, MHC molecules also affect the overall T cell repertoire during thymic selection. The relative importance of HLA class II polymorphism in exerting immunoregulatory effects by means of thymic selection of the T cell repertoire is unknown. For autoimmune diseases such as RA and IDDM, there is a need to identify a specific functional abnormality that is causing the disease before the etiological significance of the emerging associations with class II polymorphisms become clear.(ABSTRACT TRUNCATED AT 400 WORDS)

Alleles↗
PubMed2006

Transgenic expression of a CD83-immunoglobulin fusion protein impairs the development of immune-competent CD4-positive T cells.

The murine transmembrane glycoprotein CD83 is an important regulator for both thymic T cell maturation and peripheral T cell response. CD83 deficiency leads to a block in the thymic maturation of CD4-positive T cells, and interference with peripheral CD83/CD83 ligand interaction by addition of soluble CD83 suppresses immune responses in vivo and in vitro. Here we report the generation of a mouse transgenic for a fusion protein consisting of the extracellular domain of murine CD83 fused to the constant part of human IgG1 heavy chain. Thymic selection of CD4-positive T cells was unchanged in CD83Ig transgenic and in CD83Ig/OT-2 double-transgenic mice. However, thymic and peripheral CD4-positive T cells derived from CD83Ig/OT-2 transgenic mice displayed a reduced cytokine response to antigenic stimulation in vitro, whereas CD83Ig/OT-1-derived CD8-positive T cells showed normal cytokine secretion. The T cell defect was relevant in vivo, since a sub-lethal infection with Trypanosoma cruzi led to an increased parasitemia and reduced survival rate of CD83Ig transgenic mice compared to wild-type C57BL/6 mice. In contrast, in vivo application of recombinant CD83Ig did not result in an increase in parasitemia. Taken together our data suggest that thymic selection in the presence of CD83Ig leads to an intrinsic T cell defect of CD4-positive T cells resembling the phenotype described for CD4-positive T cells derived from CD83-deficient mouse strains.

Animals↗
PubMed1998

Selection of dual Valpha T cells.

Incomplete allelic exclusion of TCRa gene rearrangement permits the generation of dual Valpha T cells, though the issues of their frequency and whether both alphabeta pairs participate in thymic selection have not been resolved. Both questions have been investigated using lymphocytes from mice hemizygous at the TCRa locus and consequently unable to express two rearranged TCRa genes, as background controls. The data presented show that both the frequency of dual Valpha T cells and the relative expression levels of co-expressed Valpha chains are variable and are determined by thymic selection. Possession of a Valpha chain which is inefficiently positively selected appears to increase the likelihood that a second Valpha chain will be co-expressed, whilst the relative cell surface levels of a given pair of Valpha chains differ between CD4 and CD8 subsets. Further, for some but not all Valpha pairs, dual Valpha T cells appear to express elevated levels of surface TCR. Finally, contrary to previous claims, dual Valpha T cells do not appear to be relatively frequent amongst immature thymocytes.

Animals↗
PubMed1994

Separation of thymic education from antigen presenting functions of major histocompatibility complex class I molecules.

Participation of transmembrane (TM) and glycosyl-phosphatidylinositol (GPI) anchored H-2Db molecules in antigen presentation and thymic selection events was investigated using transgenic mice. Both GPI-Db and TM-Db can efficiently present H-Y antigen, influenza and lymphocytic choriomeningitis virus (LCMV) peptides to primed cytotoxic, H-2Db-restricted T cells. Transgenic mice expressing GPI-Db, although unable to reject TM-Db skin grafts, nevertheless generate secondary CTL responses which can lyse TM-Db-bearing targets, indicating that GPI-Db mice fail to delete all TM-Db-reactive T cells. Furthermore, double-transgenic mice bearing GPI-Db and a T-cell receptor (TcR) for H-2Db+LCMV do not positively select receptor positive, CD8+CD4- T cells. This paradoxical behaviour of GPI-Db molecules suggests that the structural requirements for antigen presentation and thymic selection by class I molecules are different and may explain why GPI-linked class I molecules, such as Qa-2, do not appear to function as restriction elements in vivo.

Animals↗
PubMed2004

Homeostatic proliferation of a Qa-1b-restricted T cell: a distinction between the ligands required for positive selection and for proliferation in lymphopenic hosts.

Naive T cells proliferate in response to self MHC molecules after transfer into lymphopenic hosts, a process that has been termed homeostatic proliferation (HP). Previous studies have demonstrated that HP is driven by low level signaling induced by interactions with the same MHC molecules responsible for positive selection in the thymus. Little is known about the homeostatic regulation of T cells specific for class Ib molecules, including Qa-1 and H2-M3, though it has been suggested that their capacity to undergo homeostatic expansion may be inherently limited. In this study, we demonstrate that naive 6C5 TCR transgenic T cells with specificity for Qa-1(b) have a capacity similar to conventional T cells to undergo HP after transfer into sublethally irradiated mice. Proliferation was largely dependent on the expression of beta(2)-microglobulin, and experiments with congenic recipients expressing Qa-1(a) instead of Qa-1(b) demonstrated that HP is specifically driven by Qa-1(b) and not through cross-recognition of classical class I molecules. Thus, the same MHC molecule that mediates positive selection of 6C5 T cells is also required for HP. Homeostatic expansion, like positive selection, occurs in the absence of a Qa-1 determinant modifier, the dominant self-peptide bound to Qa-1 molecules. However, experiments with TAP(-/-) recipients demonstrate a clear distinction between the ligand requirements for thymic selection and HP. Positive selection of 6C5 T cells is dependent on TAP function, thus selection is presumably mediated by TAP-dependent peptides. By contrast, HP occurs in TAP(-/-) recipients, providing an example where the ligand requirements for HP are less stringent than for thymic selection.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

[Regulation of thymocyte apoptosis and positive selection].

Developing T cells undergo thymic selection at the CD4+CD8+ stage. Only less than 5% of CD4+CD8+ thymocytes are positively selected to survive and differentiate into mature single positive CD4 or CD8 T cells. Positive selection requires signaling through the T cell receptors (TCR) with assistance of CD4 or CD8 coreceptor and LFA-1, but its molecular mechanism is poorly understood. By using glucocorticoids, anti-apoptotic activity was detected in CD4+CD8+ thymocytes upon proper cross-linking of TCR/CD3 complex with CD4, CD8, or LFA-1, and was mimicked by a combination of a calcium ionophore and a protein kinase C activator. Isolated CD4+CD8+ thymocytes underwent differentiation and commitment to the CD4 T cell lineage by moderate and transient stimulation with this combination of the drugs.

Animals↗