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 271 records · Page 15Linked to original sources
PubMed1991

HLA-DR and -DQ gene polymorphism in West Africans is twice as extensive as in north European Caucasians: evolutionary implications.

The HLA genes are the most polymorphic coding loci known in humans. DRB-DQA-DQB gene polymorphism was investigated by Taq I restriction fragment length polymorphism analysis in more than 700 West Africans and found to be almost twice as extensive in West Africans as in North European Caucasians. This finding indicates that Africans comprise the oldest and genetically most diverse human population and supports the hypothesis of the occurrence of a population bottleneck in the emergence of the White race. As in Caucasians, less than one-third of possible cis-encoded DQA-DQB combinations were encountered, indicating constraints on the pairing of DQ alpha and beta polypeptides. Heterozygote advantage (i.e., positive selection) was found for DRB, DQA, and DQB alleles as well as for DQA-DQB combinations. However, in West Africans as well as in North Europeans the observed frequencies of DRB-DQA-DQB homozygotes were close to neutrality expectations. Although the hypothesis that HLA polymorphism is maintained by parasite-driven overdominant selection is attractive, there is little evidence to support that view. We propose instead that one of the forces maintaining a low frequency of HLA homozygotes might be a decreased likelihood of potentially autoreactive T-cell clones escaping thymic selection in HLA heterozygotes. This would be consistent with the central role of HLA molecules as self/non-self discriminators.

Africa, Western↗
PubMed1987

Relationship among function, phenotype, and specificity in primary allospecific T cell populations: identification of phenotypically identical but functionally distinct primary T cell subsets that differ in their recognition of MHC class I and class II allodeterminants.

The goal of the present study was to evaluate the relationship among function, Lyt phenotype, and MHC recognition specificity in primary allospecific T cell populations. By using Lyt-2+ and L3T4+ T cells obtained from the same responder populations, we assessed the ability of T cells of each phenotype to generate cytotoxic effector cells (CTL) and IL 2-secreting helper T cells in response to either class I or class II MHC allodeterminants. It was found that a discordance between Lyt phenotype and MHC recognition specificity does exist in primary allospecific T cells, but only in one T cell subpopulation with limited functional potential: namely, Lyt-2+ T cells with cytotoxic, but not helper, function that recognize class II MHC alloantigens. Target cell lysis by these Lyt-2+ class II-allospecific CTL was inhibited by anti-Ia monoclonal antibodies (mAb), but not anti-Lyt-2 mAb, indicating that they recognized class II MHC determinants as their "restriction" specificity and not as their "nominal" specificity even though they were Lyt-2+. A second allospecific T cell subset with limited functional potential was also identified but whose Lyt phenotype and MHC restriction specificity were not discordant: namely, an L3T4+ T cell subset with helper, but not cytotoxic, function specific for class I MHC allodeterminants presented in the context of self-Ia. Thus, the present study demonstrates that primary allospecific T cell populations contain phenotypically identical subpopulations of helper and effector cells that express fundamentally different MHC recognition specificities. Because the recognition specificities expressed by mature T cells reflect the selection pressures they encountered during their differentiation into functional competence, these findings suggest that functionally distinct but phenotypically identical T cell subsets may be selected independently of one another during ontogeny. Thus, the existence of Lyt-2+ CTL specific for class II allodeterminants can be explained by the hypothesis that the association of Lyt phenotype with MHC recognition specificity results from the process of thymic selection that these Lyt-2+ effector cells avoid.

Animals↗
PubMed1994

Unique selection determinant in polyclonal V delta 2-J delta 1 junctional regions of human peripheral gamma delta T lymphocytes.

Human peripheral gamma delta T lymphocytes are characterized by the preferential expression of a TCR consisting of a V delta 2-J delta 1-C delta chain and a V gamma 9-J gamma 1.2-C gamma 1 chain, which are virtually absent on thymocytes. Here we report the identification of a unique selection determinant that is located in the polyclonal V delta 2-J delta 1 junctional regions of peripheral gamma delta T lymphocytes. The selection determinant was discovered by the presence of an invariant T nucleotide at the relative second position of the V delta 2-J delta 1 junctional regions of peripheral polyclonal gamma delta T lymphocytes. Comparison of published sequences from peripheral gamma delta T lymphocytes confirmed the presence of this invariant T nucleotide (90%) in healthy individuals and in patients with various diseases. Translation of the relative first codon of the V delta 2-J delta 1 junctional regions revealed strikingly high frequencies of the homologous hydrophobic amino acids leucine (46%), valine (35%), and isoleucine (5%) at this position. The invariant T nucleotide was absent in polyclonal thymocytes and out-of-frame V delta 2-J delta 1 junctional regions, which proves that selection occurred at the protein level and not at the genomic level. No selection determinant could be identified in V gamma 9-J gamma 1.2 junctional regions, but the frequently occurring invariable, so-called canonical junctional region provided evidence for biased recombination processes. Although the obtained data do not allow discrimination between thymic selection and/or peripheral Ag-driven expansion, the identification of a strong selection determinant consisting of only one amino acid at a fixed position in V delta 2-J delta 1 junctional regions of virtually all peripheral polyclonal V delta 2/V gamma 9 T lymphocytes provides a new perception of TCR specificity and selection processes at the TCR protein level.

Amino Acid Sequence↗
PubMed1993

Selection is not required to produce invariant T-cell receptor gamma-gene junctional sequences.

Recombination of V-, D- and J-gene segments can generate an enormous diversity of T-cell antigen receptor (TCR) gene sequences. Although many gamma delta T cells fully exploit this diversification process, those in the epidermal and vaginal epithelium do not, predominantly expressing invariant gamma delta receptors in which the V-(D)-J junctional sequences in almost all the productive rearrangements are identical. The almost exclusive use of identical TCRs by cells in these sites is thought to reflect recognition of a stress-induced autologous antigen. To explain the prevalence of the invariant junctional sequences, it has been proposed that thymic selection operates on a population of originally diverse progenitor cells, resulting in a homogeneous repertoire. Alternatively the invariant sequences may result from biases in the recombination machinery in the fetal thymic progenitors of these cells. We report here the use of mice into which mutated TCR gamma-gene rearrangement substrates have been introduced as transgenes to demonstrate directly that the canonical TCR V gamma 3-J gamma 1 and V gamma 4-J gamma 1 sequences occur at high frequency in the absence of the possibility of selection for the protein products.

Animals↗
PubMed2002

Glucocorticoid (GC) sensitivity and GC receptor expression differ in thymocyte subpopulations.

Positive and negative selection steps in the thymus prevent non-functional or harmful T cells from reaching the periphery. To examine the role of glucocorticoid (GC) hormone and its intracellular receptor (GCR) in thymocyte development we measured the GCR expression in different thymocyte subpopulations of BALB/c mice with or without previous dexamethasone (DX), anti-CD3 mAb, RU-486 and RU-43044 treatment. Four-color labeling of thymocytes allowed detection of surface CD4/CD8/CD69 expression in parallel with intracellular GCR molecules by flow cytometry. Double-positive (DP) CD4+CD8+ thymocytes showed the lowest GCR expression compared to double-negative (DN) CD4-CD8- thymocytes and mature single-positive (SP) cells. DX treatment caused a concentration-dependent depletion of the DP cell population and increased appearance of mature SP cells with reduced GCR levels. GCR antagonists (RU-486 or RU-43044) did not influence the effect of DX on thymocyte composition; however, RU-43044 inhibited the high-dose GC-induced GCR down-regulation in SP and DN cells. GCR antagonists alone did not influence the maturation of thymocytes and receptor numbers. Combined low-dose anti-CD3 mAb and DX treatment caused an enhanced maturation (positive selection) of thymocytes followed by the elevation of CD69+ DP cells. The sensitivity of DP thymocytes with a GCRlow phenotype to GC action and the ineffectiveness of the GCR antagonist treatment may reflect a non-genomic GC action in the thymic selection steps.

Animals↗
PubMed1994

Role of TCR zeta chain in T cell development and selection.

Signals mediated by the T cell receptor (TCR) are required for thymocyte maturation and selection. To examine the role of TCR zeta chain signals in development, TCR expression was restored in zeta-deficient mice with transgenic zeta chains that partially or completely lacked sequences required for signal transduction. The zeta chain played a role in thymic development by promoting TCR surface expression, but zeta-mediated signals were not essential because TCRs that contained signaling-deficient zeta chains promoted T cell maturation and transduced signals associated with thymic selection.

Amino Acid Sequence↗
PubMed1997

MHC-derived peptides and the CD4+ T-cell repertoire: implications for autoimmune disease.

The receptor repertoire of peripheral CD4+ cells is primarily determined by selection processes in the thymus. These result in the positive selection of T cells whose receptors weakly recognize self-peptides restricted by class II self-MHC heterodimers. A majority of such self-peptide partial agonists are likely to be derived from self-MHC molecules. It is suggested that these thymically selected, weakly autoreactive T cells may subsequently be stimulated by peripheral exposure to microbially derived agonists that 'mimic' corresponding self-MHC peptides. In turn, 'molecular mimicry' between microbial agonists and tissue-specific self-peptides may lead to T-cell-mediated autoimmune disease. Hence such disease may reflect 'three-way mimicry' between peptides of respectively target tissue, pathogen and self-MHC (or other self-peptide dominantly presented in the thymus). This hypothesis accounts for the role of MHC haplotype in determining susceptibility to (or protection from) autoimmune disease. Direct evidence is presented in favour of the model as applied to diseases such as rheumatoid arthritis, autoimmune uveitus and autoimmune diabetes. Strong circumstantial evidence, based primarily on sequence similarities, is also presented for other autoimmune diseases. However, it is noted that the statistics of database searches, and the lack of predictable correlation between sequence similarity and T-cell cross-reactivity, require that such evidence be substantiated by further direct experiment.

Alleles↗
PubMed1993

T lymphocyte signalling defects and immunodeficiency due to the lack of CD3 gamma.

A selective CD3 gamma defect, involving point mutations in both the paternal and the maternal genes, has been analyzed. The CD3 gamma defect affected two brothers of a four sibs family; one of them died at the age of 3 of a viral pneumonia with concomitant autoimmune features (Haemolytic anaemia and gut epithelial cell autoantibodies), whereas the other is still alive at the age of 10 with relatively mild infection episodes. In this work, the effects of the absence of the CD3 gamma chain in the structure and signal transduction of the T-cell receptor (TCR)/CD3 complex and in the selection and function of T lymphocytes were studied. The absence of CD3 gamma did not prevent the expression of certain amounts of TCR/CD3 complexes on the surface of T lymphocytes. This suggests the existence of at least two TCR/CD3 isoforms in T cells, either with or without CD3 gamma. A persistent low proportion of CD8+ T cells, not functional in vitro (they were unable to proliferate) and probably in vivo (associated to a lethal viral pneumonia), was observed. In contrast, the proportion of CD4+ T cells was not altered, and they were functional both in vitro (they showed a normal proliferation and a low, but detectable, increase of cytosolic Ca2+ in response to anti-TCR/CD3 stimuli, although the production of IL-2 was impaired) and in vitro (they normally helped B cells). These results show that the absence of CD3 gamma affects the selection and function of cytotoxic, but apparently not helper, T lymphocytes, although the possibility that the CD4+ T cells represent a specific subpopulation can not be ruled out. They also suggest that the interactions of the TCR/CD3 complex with its co-receptors during thymic selection and antigen recognition in the periphery may be asymmetrical, with CD8 interacting through CD3 gamma and, probably, CD4 through the homologous CD3 delta.

Autoimmunity↗
PubMed1996

Identification and cellular distribution of the rat interleukin-2 receptor beta chain: induction of the IL-2R alpha- beta+ phenotype by major histocompatibility complex class I recognition during T cell development in vivo and by T cell receptor stimulation of CD4+8+ immature thymocytes in vitro.

A mouse monoclonal antibody (mAb) to the rat interleukin-2 receptor beta (IL-2R beta) chain was generated using IL-2R beta cDNA-transfected mouse L929 cells for immunization and differential screening. This antibody, called L316, detects a cell surface protein with an apparent molecular mass of about 80 kDa. In peripheral lymphoid organs of young adult rats, IL-2R beta expression is restricted to T and natural killer (NK) cells, and less than 10% of IL-2R beta+ cells co-express the IL-2R alpha chain. IL-2R beta was detected on all NKRP-1hi (NK-) and NKRP-1lo cells (T-lineage cells of unknown function), most peripheral gama delta T cells and on 30-40 % of CD8 and 10 % of CD4 alpha beta T cells. In the adult rat thymus, mAb L316 detects a small subset (about 1%) of predominantly IL-2R alpha- cells which express cell surface markers characteristic of mature T lymphocytes and contain a high proportion of CD4-8- and CD4-8+ alpha beta T cell receptor (TCR)+ thymocytes. TCR-V usage suggests that major histocompatibility complex (MHC) class I plays a more important role than MHC class II in the selection of these cells. On immature CD4+8+ rat thymocytes, IL-2R beta cell surface expression is readily induced by TCR stimulation in vitro, supporting the idea that in vivo, the IL-2R beta+ phenotype is the the result of TCR engagement during thymic selection.

Animals↗
PubMed1991

T cell receptor-mediated selection of functional rat CD8 T cells from defined immature thymocyte precursors in short-term suspension culture.

Recent results have indicated that positive and negative repertoire selection act on the major population of CD4,8 double-positive (DP) thymocytes that express 5-10-fold less T cell receptor (TCR) than mature T cells (i.e., they are TCRlow). Since DP cells obtained ex vivo are heterogeneous with regard to their stage within thymic selection, a homogeneous population of virgin DP cells suitable for selection studies was generated in vitro from their immediate precursors, the CD8 single-positive (SP) immature blast cells. To mimic TCR-mediated selection signals, these virgin DP cells were then cultured for another 2 d in the presence of immobilized anti-TCR monoclonal antibodies with or without interleukin 2 (IL-2). Daily monitoring of recovery and phenotype showed that without TCR stimulation, the cells remained DP and became small, TCRlow cells that were lost with a half-life of 1 d, regardless of the presence of IL-2. TCR stimulation resulted in rapid downregulation of CD4 and CD8, maintenance of a larger cell size, and induction of the CD53 antigen that marks mature and CD4,8 double-negative rat thymocytes. In the absence of IL-2, viability decreased as rapidly as without TCR stimulation. Addition of IL-2 rescued TCR-stimulated virgin DP cells and prevented CD8 downregulation, so that 50-80% of input DP cells were recovered after 2 d as CD4-8+53+ cells. After release from modulation, these in vitro generated CD8 SP cells quantitatively upregulated the TCR to the TCRhigh phenotype and were readily induced to proliferate and exhibit cytotoxic T lymphocyte (CTL) activity in a polyclonal readout. Evidence is presented implicating an IL-2 receptor (IL-2R) not containing the p55 chain (i.e., most likely the p70 intermediate affinity IL-2R) in the TCR plus IL-2-driven in vitro differentiation of virgin DP cells towards the mature CD8 SP phenotype.

Animals↗
PubMed2005

Programmed death-1 (PD-1):PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes.

Positive selection during thymocyte development is driven by the affinity and avidity of the TCR for MHC-peptide complexes expressed in the thymus. In this study, we show that programmed death-1 (PD-1), a member of the B7/CD28 family of costimulatory receptors, inhibits TCR-mediated positive selection through PD-1 ligand 1 (PD-L1):PD-1 interactions. Transgenic mice that constitutively overexpress PD-1 on CD4+CD8+ thymocytes display defects in positive selection in vivo. Using an in vitro model system, we find that PD-1 is up-regulated following TCR engagement on CD4+CD8+ murine thymocytes. Coligation of TCR and PD-1 on CD4+CD8+ thymocytes with a novel PD-1 agonistic mAb inhibits the activation of ERK and up-regulation of bcl-2, both of which are downstream mediators essential for positive selection. Inhibitory signals through PD-1 can overcome the ability of positive costimulators, such as CD2 and CD28, to facilitate positive selection. Finally, defects in positive selection that result from PD-1 overexpression in thymocytes resolve upon elimination of PD-L1, but not PD-1 ligand 2, expression. PD-L1-deficient mice have increased numbers of CD4+CD8+ and CD4+ thymocytes, indicating that PD-L1 is involved in normal thymic selection. These data demonstrate that PD-1:PD-L1 interactions are critical to positive selection and play a role in shaping the T cell repertoire.

Animals↗
PubMed1998

Analysis of the role of variation of major histocompatibility complex class II expression on nonobese diabetic (NOD) peripheral T cell response.

The current paradigm of major histocompatibility complex (MHC) and disease association suggests that efficient binding of autoantigens by disease-associated MHC molecules leads to a T cell-mediated immune response and resultant autoimmune sequelae. The data presented below offer a different model for this association of MHC with autoimmune diabetes. We used several mouse lines expressing different levels of I-Ag7 and I-Ak on the nonobese diabetic (NOD) background to evaluate the role of MHC class II in the previously described NOD T cell autoproliferation. The ratio of I-Ag7 to I-Ak expression correlated with the peripheral T cell autoproliferative phenotype in the mice studied. T cells from the NOD, [NOD x NOD. I-Anull]F1, and NOD I-Ak transgenic mice demonstrated autoproliferative responses (after priming with self-peptides), whereas the NOD.H2(h4) (containing I-Ak) congenic and [NOD x NOD. H2(h4) congenic]F1 mice did not. Analysis of CD4(+) NOD I-Ak transgenic primed lymph node cells showed that autoreactive CD4(+) T cells in the NOD I-Ak transgenic mice were restricted exclusively by I-Ag7. Considered in the context of the avidity theory of T cell activation and selection, the reported poor peptide binding capacity of NOD I-Ag7 suggested a new hypothesis to explain the effects of MHC class II expression on the peripheral autoimmune repertoire in NOD mice. This new explanation suggests that the association of MHC with diabetes results from "altered" thymic selection in which high affinity self-reactive (potentially autoreactive) T cells escape negative selection. This model offers an explanation for the requirement of homozygous MHC class II expression in NOD mice (and in humans) in susceptibility to insulin-dependent diabetes mellitus.

Animals↗
PubMed2004

Antigen-induced tolerance by intrathymic modulation of self-recognizing inhibitory receptors.

CD1d-restricted invariant natural killer T cell (iNKT cells) have a limited T cell receptor (TCR) repertoire and share characteristics common to T cells and natural killer cells. While intrathymic selection facilitates the production of T cells carrying self major histocompatibility complex-restricted TCRs, natural killer cells carry an appropriate repertoire of self major histocompatibility complex-recognizing receptors to avoid self-reactivity. Here we show that chronic exposure to specific glycolipid antigen resulted in iNKT cell disappearance and thymus-dependent repopulation of iNKT cells with increased expression of inhibitory Ly-49 molecules that resulted in impaired responsiveness. Thymic selection of peripheral Ly-49-expressing iNKT cell repertoire inhibited cytokine production and other functions in vivo. These observations emphasize the acquisition of self-recognizing inhibitory receptors on NKT cells as a previously unknown mechanism of thymic tolerance after chronic antigen exposure.

Animals↗
PubMed2005

Regulatory CD4+CD25+ cells reverse imbalances in the T cell pool of bone marrow transplanted TGepsilon26 mice leading to the prevention of colitis.

BACKGROUND AND AIMS: Erroneous thymic selection of developing T lymphocytes may be responsible for the expansion of self reactive T cells or may contribute to the absence of regulatory T cells important in controlling peripheral inflammatory processes. Colitis in bone marrow (BM) transplanted Tgepsilon26 mice is induced by abnormally activated T cells developing in an aberrant thymic microenvironment. We investigated the protective role of regulatory CD4+CD25+ T cells in this model. METHODS: BM from (C57BL/6 x CBA/J) F1 mice was transplanted into specific pathogen free Tgepsilon26 mice (BM-->Tgepsilon26). Transplanted mice received no cells (control), sorted CD4+CD25+, or CD4+CD25- cells from mesenteric lymph nodes (MLN) of normal mice. MLN cell subsets were analysed using membrane markers. Cytokine secretion of MLN cells was measured using intracellular cytokine staining and cytokine secretion in anti-CD3 stimulated cell cultures. Colitis was measured by histological scores. RESULTS: CD4+CD25+ cells were reduced in the MLNs of BM-->Tgepsilon26 mice. Transfer of regulatory CD4CD4+CD25+ but not of CD4+CD25- cells reduced the number of MLN CD4+ T cells in BM-->Tgepsilon26 recipients and increased the number of MLN CD8+ cells, thereby normalising the CD4+/CD8+ ratio. CD4+CD25+ but not CD4+CD25- cell transfer into BM-->Tgepsilon26 mice reduced the number of tumour necrosis factor alpha+ CD4+ cells and increased the secretion of transforming growth factor beta by MLN cells. Transfer of 3 x 10(5) CD4+CD25+ cells after BM transplantation into Tgepsilon26 mice prevented colitis whereas CD4+CD25- cells had no protective effect. CONCLUSIONS: These results suggest that defective selection or induction of regulatory T cells in the abnormal thymus is responsible for the development of colitis in BM-->Tgepsilon26 mice. Transfer of CD4+CD25+ cells can control intestinal inflammation in BM-->Tgepsilon26 mice by normalising the number and function of the MLN T cell pool.

Animals↗
PubMed2002

Positive selection of a Qa-1-restricted T cell receptor with specificity for insulin.

The phenotype and development of T cells from transgenic mice expressing a T cell receptor with specificity for insulin presented by the MHC class Ib molecule Qa-1(b) was investigated. Peripheral T cells from the transgenic mice express CD8 and, after activation, kill Qa-1(b)-positive lymphoid target cells in the presence of soluble insulin. Thymic selection requires expression of Qa-1(b) but not the dominant Qa-1-associated peptide, Qdm. In contrast to conventional T cells, selection is at least as efficient when the selecting ligand is expressed only on hematopoietic lineage cells as compared to expression on epithelial cells in the thymus. Our findings suggest that there is a dedicated population of Qa-1-restricted T cells that are selected by interaction with Qa-1 and that the cellular requirements for selection may differ from conventional T cells.

Animals↗
PubMed1992

Intrathymic activation events and the generation of IL-4 producer CD4+8- thymocytes.

The generation of mouse CD4+8- thymocytes appears to involve an activation process. CD69, an early activation marker, is first expressed on 3% of TCRlo/med double-positive thymocytes and peaks (70-90%) at the HSAhi TCRmed CD4+8lo and the HSAhi TCRhi CD4+8- stages, before being downmodulated. CD44, a marker of a later stage of activation is selectively expressed at the HSAlo CD4+8- stage. Functional changes associated with the late activated state, such as the transient acquisition of the potential to secrete IL-4 upon stimulation, are also induced at the HSAlo CD4+8- stage and are still evident after export to the periphery. During thymic selection, interactions of different affinities between TCR/CD4 and self ligand/MHC class II, are likely to induce different degrees of activation. This may impart different functional capabilities--such as the potential to secrete IL-4--to a subset of emerging CD4+ T lymphocytes that express TCRs with intermediate affinities for self. Such a pathway may be involved in the maintenance of tolerance and the prevention of some deleterious autoimmune reactions.

Animals↗
PubMed1992

Retinoic acids inhibit activation-induced apoptosis in T cell hybridomas and thymocytes.

Apoptosis is induced in immature thymocytes and T cell hybridomas upon stimulation via the TCR/CD3 complex. This phenomenon appears to be related to negative selection of T cell clones in the thymus. In T cell hybridomas, it has been shown that glucocorticoids inhibit TCR/CD3-mediated apoptosis, whereas glucocorticoids alone induce apoptosis. All-trans-retinoic acid (RA) at 0.1 to 10 microM also inhibited TCR/CD3-mediated apoptosis assessed by DNA fragmentation and cytolysis, but RA alone hardly induced apoptosis. RA enhanced the effects of glucocorticoids to induce apoptosis and to inhibit TCR/CD3-mediated apoptosis. TCR/CD3-mediated stimulation can be mimicked by the combination of ionomycin, a calcium ionophore, and PMA, an activator of protein kinase C, and the combination-induced DNA fragmentation was also inhibited by RA. RA, however, failed to inhibit the combination-induced increase in intracellular Ca2+ concentration or the combination-induced translocation of protein kinase C from the cytosolic fraction to the particulate fraction. Time course studies of RA addition into the culture indicated that a 3- to 6-h delay in the addition of RA did not reduce its inhibitory effect on anti-CD3-induced DNA fragmentation. These results suggest that RA interferes with the apoptotic process at some point after its initiation stage. It has been suggested that negative selection involves not only TCR/CD3-mediated signals but also LFA-1-mediated signals. RA at 0.01 to 1 microM significantly inhibited the induction of thymocyte apoptosis by co-immobilized mAb to CD3 and LFA-1 molecules. RA by itself hardly induced apoptosis, but enhanced glucocorticoid-induced apoptosis. The results suggest that thymic selection might be influenced by RA at near-physiologic concentrations. The receptors of glucocorticoids and RA belong to the erbA oncogene-related steroid hormone receptor superfamily. Thyroid hormones and 1 alpha,25-dihydroxy vitamin D3, whose receptors also belong to the superfamily, failed to modulate apoptosis in both T cell hybridomas and thymocytes.

Animals↗
PubMed2006

Impaired generation of CD8+ thymocytes in Ets-1-deficient mice.

The Ets family of transcription factors function as key regulators of multiple aspects of immune cell development and function. To date, Ets-1 has been implicated in regulating early stages of thymic maturation and lymphocyte function and homeostasis. This report describes a novel role for Ets-1 in supporting later stages of thymic selection, in that positive selection of MHC class I-restricted CD4+CD8+ double-positive thymocytes is markedly inhibited in mice expressing a hypomorphic allele of Ets-1. This effect is thymocyte intrinsic, as Ets-1 mutant thymocytes fail to efficiently generate CD8+ single-positive thymocytes in mixed bone marrow chimeric backgrounds. Although peripheral CD8+ T cells are present in Ets-1 mutant mice, both CD4+ and CD8+ subsets contain an elevated proportion of cells with an effector memory (CD62L-CD44+) phenotype. In addition, while thymic expression of Thy1 is relatively normal, peripheral T cells isolated from Ets-1 mutant mice display a striking loss of Thy1 expression. These data identify Ets-1 as a key transcription factor regulating thymocyte positive selection and lineage commitment of MHC class I-restricted thymocytes.

Animals↗