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Results for “thymic selection”

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PubMed1991

Requirement for positive selection of gamma delta receptor-bearing T cells.

The alpha beta and gamma delta T cell receptors for antigen (TCR) delineate distinct T cell populations. TCR alpha beta-bearing thymocytes must be positively selected by binding of the TCR to major histocompatibility complex (MHC) molecules on thymic epithelium. To examine the requirement for positive selection of TCR gamma delta T cells, mice bearing a class I MHC-specific gamma delta transgene (Tg) were crossed to mice with disrupted beta 2 microglobulin (beta 2M) genes. The Tg+beta 2M- (class I MHC-) offspring had Tg+ thymocytes that did not proliferate to antigen or Tg-specific monoclonal antibody and few peripheral Tg+ cells. This is evidence for positive selection within the gamma delta T cell subset.

Animals↗
PubMed2002

CD40 ligand functions non-cell autonomously to promote deletion of self-reactive thymocytes.

CD40 ligand (CD40L)-deficient mice have been shown to have a defect in negative selection of self-reactive T cells during thymic development. However, the mechanism by which CD40L promotes deletion of autoreactive thymocytes has not yet been elucidated. We have studied negative selection in response to endogenous superantigens in CD40L-deficient mice and, consistent with previous reports, have found a defect in negative selection in these mice. To test the requirement for expression of CD40L on T cells undergoing negative selection, we have generated chimeric mice in which CD40L wild-type and CD40L-deficient thymocytes coexist. We find that both CD40L wild-type and CD40L-deficient thymocytes undergo equivalent and efficient negative selection when these populations coexist in chimeric mice. These results indicate that CD40L can function in a non-cell-autonomous manner during negative selection. Deletion of superantigen-reactive thymocytes was normal in B7-1/B7-2 double-knockout mice, indicating that CD40-CD40L-dependent negative selection is not solely mediated by B7 up-regulation and facilitation of B7-dependent T cell signaling. Finally, although the absence of CD40-CD40L interactions impairs negative selection of autoreactive CD4(+) and CD8(+) cells during thymic development, we find that self-reactive T cells are deleted in the mature CD4(+) population through a CD40L-independent pathway.

Animals↗
PubMed2014

Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus.

The contribution of thymic antigen-presenting-cell (APC) subsets in selecting a self-tolerant T cell population remains unclear. We show that bone marrow (BM) APCs and medullary thymic epithelial cells (mTECs) played nonoverlapping roles in shaping the T cell receptor (TCR) repertoire by deletion and regulatory T (Treg) cell selection of distinct TCRs. Aire, which induces tissue-specific antigen expression in mTECs, affected the TCR repertoire in a manner distinct from mTEC presentation. Approximately half of Aire-dependent deletion or Treg cell selection utilized a pathway dependent on antigen presentation by BM APCs. Batf3-dependent CD8α⁺ dendritic cells (DCs) were the crucial BM APCs for Treg cell selection via this pathway, showing enhanced ability to present antigens from stromal cells. These results demonstrate the division of function between thymic APCs in shaping the self-tolerant TCR repertoire and reveal an unappreciated cooperation between mTECs and CD8α⁺ DCs for presentation of Aire-induced self-antigens to developing thymocytes.

Animals↗
PubMed1991

The relationship between MHC restricted and allospecific T cell recognition.

The existence in the mature T cell repertoire of a high precursor frequency of cells which recognise allogeneic MHC molecules appears to contradict the well-established dogma of positive selection for self MHC restriction. In order to explore the possibility that alloreactive cells are derived from a fraction of the repertoire that is not self-MHC-restricted, the contribution of in vivo-primed T cells to "primary" alloresponses was investigated. Peripheral blood T cells were separated into virgin and memory populations by sorting for low and high levels of LFA-3 expression, and their proliferative responses to MHC incompatible stimulator cells was quantitated. The results demonstrated that approximately half of a "primary" alloresponse is contributed by previously primed T cells that, by definition, must be self-MHC restricted. Furthermore it was possible to define the original MHC-restricted antigen specificity of two T cell clones raised against the allospecific HLA-DR1 from a DR4Dw4/DRw13DW19 responder. The emerging consensus view that anti-MHC alloreactive T cells, like antigen-specific T cells, are specific for MHC/peptide complexes, and have a parental self-MHC restriction, begs a structural explanation. Comparison of multiple DR beta 1 domain sequences reveals that DR molecules fall into groups that have extensive homology in the residues on the beta 1 domain alpha-helix that are predicted to point up towards the T cell receptor (histotopic), and thus to determine MHC restriction. Given that the DR alpha chain is invariant this creates the possibility that anti-DR allorecognition can mimic self-restricted recognition. Within these groups of histotopically similar DR products there are multiple differences in the peptide-binding residues that lie on the inner aspects of the alpha-helix or on the floor of the antigen-binding groove. As a consequence, it is predicted that a different array of endogenous peptides will be bound, due to determinant selection. Thus, allorecognition within these groups may result from the recognition of endogenous peptides that are bound by stimulator but not by responder MHC products, seen in a self-restricted manner. In combinations where histotopic similarity does not exist, allorecognition may be best explained by the chance occurrence of a receptor selected for intermediate affinity for thymically expressed MHC molecules having a higher affinity for an allogeneic histotope. Such a receptor would have been deleted in a thymus expressing the allospecificity, but would be perceived as "safe" in the absence of this MHC product.

Antigen-Antibody Reactions↗
PubMed1982

Host endocrine status mediates oncogenesis: leukemia virus-induced carcinomas and reticulum cell sarcomas in acyclic or normal mice.

A highly selective leukemogenic virus obtained from thymic lymphosarcomas (LS) of C57BL/6 mice was inoculated intraperitoneally into normal or gonadectomized C57BL/6 male mice and into normal or masculinized, acyclic, Charles River (CR) outbred female mice. This virus induced early onset of LS in both normal and gonadectomized C57BL/6 mice. The same virus induced a relatively late onset of many mammary adenocarcinomas in the normal CR mice and ovary adenocarcinomas and systemic neoplasms (LS and reticulum cell neoplasms) in the acyclic females. Topography, histopathology and the average latent period of the tumors were completely different between the normal and the acyclic females. This is consistent with the idea that a leukemia virus can induce tumors other than leukemia and that permanent alterations of the physiological hormonal cyclicity plays a major role in determining whether or on which target cells the ubiquitous virus will exert its carcinogenic action.

Adenocarcinoma↗
PubMed1998

T lymphopenia in obese diabetic (db/db) mice is non-selective and thymus independent.

Although C57BL/KsJ db/db mice, an animal model of non-insulin-dependent diabetes mellitus (NIDDM), develop T lymphopenia in association with the progression of NIDDM, the T lymphopenia has not been fully investigated. In this study, to elucidate how and why T lymphopenia develops in db/db mice, T-lymphocyte subsets in spleen and thymus were longitudinally examined by flow cytometry and the effects of thymectomy and dietary restriction on the development of T lymphopenia were evaluated. After 8 weeks of age, when obese diabetes progresses, T lymphopenia in both spleen and thymus developed and all T-lymphocyte subsets examined were similarly reduced compared to lean (-/X) littermates, indicating non-selective T lymphopenia in db/db mice. Thymectomy performed at 5 wk of age, when neither T lymphopenia nor NIDDM yet presents, had no significant effect on the development of T lymphopenia. Furthermore, pair feeding until 30 weeks of age produced normal body weight and normoglycemia with still marked hyperinsulinemia, but failed to correct T lymphopenia in db/db mice. In conclusion, our results suggest that T lymphopenia may develop non-selectively and independently of either thymic dysfunction or obese diabetes in db/db mice.

Animals↗
PubMed2002

Analysis of HLA-G expression in breast cancer tissues.

Among the different mechanisms by which cancer can elude the immune system, alterations in the expression of human leukocyte antigen (HLA) class I molecules on tumor cells may play a crucial role by impairing the HLA molecules interaction with T and natural killer (NK) cells specific receptors. More recently, aberrant expression of HLA-G has been described in different tumor tissues in addition to HLA class I downregulation. The HLA-G molecule is a nonclassical HLA class I antigen selectively expressed by trophoblast and thymic epithelial cells. Several studies reported that the HLA-G function might represent an additional mechanism of tumor immune escape, mainly inhibiting NK and cytotoxic T-cell activity. Here we report the analysis of HLA-G expression both at RNA level by reverse transcriptase-polymerase chain reaction and at protein level by Western blot and immunohistochemistry in 25 breast cancer patient tissues. The aim of this study was to elucidate the HLA-G gene expression pattern in breast tumor tissues and correlate it with HLA class I alterations. Our results demonstrated that HLA-G molecules expression was never found even in a group of patients revealing HLA class I total loss, and that HLA-G is not expressed in breast cancer tissue with a low-tumor grade (G1-G2) and minimal stromal contamination.

Blotting, Western↗
PubMed1998

Residual MHC class II expression on mature dendritic cells and activated B cells in RFX5-deficient mice.

Patients with major histocompatibility complex class II (MHC-II) deficiency are known to carry mutations in either the RFX complex or the trans-activator CIITA. While the pivotal role of CIITA for MHC-II gene transcription is supported by the essential absence of MHC-II molecules in CIITA-deficient mice, we demonstrate here that RFX5-/- mice retain expression of MHC-II in thymic medulla, mature dendritic cells, and activated B cells. Nevertheless, RFX5-/- mice develop a severe immunodeficiency due to the lack of MHC-II in thymic cortex, failure of positive selection of CD4+ T cells, and absence of MHC-II on resting B cells and resident or IFNgamma-activated macrophages. This differential requirement for CIITA and RFX5 in subsets of antigen-presenting cells may be specific for the mouse; it may, however, also exist in humans without having been noticed so far.

Animals↗
PubMed1993

Comparison of peptides bound to spleen and thymus class II.

In the past we and others have suggested that positive selection of developing thymocytes may depend upon interaction between the alpha beta receptors on these cells and major histocompatibility complex (MHC) proteins bound to peptides found uniquely in the selecting tissue, thymus cortical epithelium. To test this hypothesis, peptides were isolated from MHC class II proteins of spleen, thymus cortical plus medullary epithelium, or thymus cortical epithelium alone. The results showed that the major peptides bound to class II on thymus cortical epithelium were also associated with spleen class II. Some peptides could only be detected in isolates from spleen, probably because of differences in the distribution or uptake of the donor proteins between spleen and thymus. Thus, although we found some tissue-specific distribution of self-peptides, our data suggest that there are no fundamental differences among these tissues in the occupancy of class II MHC by self-peptides. These results limit hypotheses which depend on a specialized mechanism of peptide generation and/or MHC class II loading to account for the positive selection of T cells on thymic cortical epithelium.

Amino Acid Sequence↗
PubMed1996

Development of insulitis without diabetes in transgenic mice lacking perforin-dependent cytotoxicity.

It is widely accepted that T cells play an important role in the destruction of beta cells leading to autoimmune type I diabetes, but the involved effector mechanisms have remained unclear. We addressed this issue by testing the role of perforin-dependent cytotoxicity in a disease model involving transgenic mice expressing glycoprotein of lymphocytic choriomeningitis virus (LCMV-GP) in the beta cells of the endocrine pancreas. In such mice, LCMV infection leads to a potent LCMV-GP-specific T cell response resulting in rapid development of diabetes. We report here that in perforin-deficient LCMV-GP transgenic mice, LCMV infection failed to induce diabetes despite the activation of LCMV-GP-specific T cells. Deletion of nu beta 6+ T cells in Mls-1a perforin-deficient mice and the activation of LCMV-GP-specific T cells in perforin-deficient LCMV-GP transgenic mice, however, indicated that thymic tolerance induction by negative selection was not affected by the disruption of the perforin gene and that there is no fundamental difference between the T cell repertoires of normal control and perforin-deficient mice. In addition, adoptive transfer of LCMV-GP-specific TCR transgenic perforin-deficient T cells activated by LCMV-GP recombinant vaccinia virus led to marked insulitis with infiltration of CD4+ and CD8+ T cells without the development of diabetes. These findings indicate that perforin-dependent cytotoxicity is not required for the initiation of insulitis but is crucial for the destruction of beta cells in the later phase of the disease process. Other mechanisms or soluble factors present in the inflammatory islet infiltrate apparently lack the ability to efficiently induce diabetogenic beta cell damage.

Animals↗
PubMed1998

A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes.

Members of the tumour necrosis factor receptor family that contain a death domain have pleiotropic activities. They induce apoptosis via interaction with intracellular FADD/MORT1 and trigger cell growth or differentiation via TRADD and TRAF molecules. The impact of FADD/MORT1-transduced signals on T lymphocyte development was investigated in transgenic mice expressing a dominant negative mutant protein, FADD-DN. Unexpectedly, FADD-DN enhanced negative selection of self-reactive thymic lymphocytes and inhibited T cell activation by increasing apoptosis. Thus signalling through FADD/MORT1 does not lead exclusively to cell death, but under certain circumstances can promote cell survival and proliferation.

Adaptor Proteins, Signal Transducing↗
PubMed1991

Interleukin 7 preferentially supports the growth of gamma delta T cell receptor-bearing T cells from fetal thymocytes in vitro.

Murine fetal thymus cells were cultured with various interleukins (IL-1, 2, 3, 4, 5, 6, and 7) in the absence or presence of phorbol 12-myristate 13-acetate (PMA), and it was found that only IL-4 and IL-7 induced a prominent proliferative response in the presence of PMA. A large proportion of cells grown in the cultures of fetal thymus cells (days 15 and 17 of gestation) stimulated with PMA plus IL-4 or with PMA plus IL-2 remained CD4-CD8-. In marked contrast, nearly 70% of the cells generated in the cultures of the same fetal thymocytes stimulated with PMA plus IL-7 expressed CD8 on their surface. Approximately 30% of these cells expressed TCR gamma, delta, whereas TCR alpha beta+ cells were virtually undetectable. The cells grown in cultures stimulated with PMA plus IL-7 comprised three populations: CD4-Lyt-2-3-, CD4-Lyt-2 + Lyt-3- and CD4-Lyt-2 + Lyt-3+, and that TCR gamma delta+ T cells were found in all three populations. It was also found that the addition of IL-7 in the culture of adult CD4-CD8- thymocytes on the monolayer of a thymic stromal cell line, which selectively promotes the generation of alpha beta T cells, resulted in the generation of gamma delta T cells. These results strongly suggest that IL-7 plays an important role in the development of gamma delta T cells.

Animals↗
PubMed1996

The aging immune system: primer and prospectus.

Changes in T lymphocyte populations underlie much of the age-related decline in the protective immune response. Aging leads to the replacement of virgin T cells by memory T cells and to the accumulation of cells with signal transduction defects. Studies of antibody gene assembly, accessory cell function, post-thymic T cell development, skewed selection of T cell receptor repertoire, and the clinical concomitants of immune senescence will shed new light on the causes and consequences of age-dependent immune failure.

Aged↗
PubMed1994

Radiation leukemia virus-induced thymic lymphomas express a restricted repertoire of T-cell receptor V beta gene products.

We have investigated the phenotypic changes that take place during the process of neoplastic transformation in the thymocytes of C57BL/Ka mice infected by the radiation leukemia virus (RadLV). By the combined use of antibodies against the envelope glycoprotein gp70 of RadLV, the transformation-associated cell surface marker 1C11, and the CD3-T-cell receptor (TCR) complex, we found that in the RadLV-infected thymus, the earliest expression of viral gp70 is in 1C11hi cells; a small but significant percentage of these cells also express CD3. A first wave of viral replication, manifested by the expression of high levels of gp70 in thymocytes (over 70% positive), reaches a peak at 2 weeks; during this period, no significant changes are observed in the expression of 1C11 or CD3. The population of gp70+ cells is drastically reduced at 3 to 4 weeks after infection. However, a second cohort of gp70+ cells appears after 4 weeks, and these cells express high levels of 1C11 and TCR determinants as well. RadLV-induced lymphomas differ from normal thymocytes in their CD4 CD8 phenotype, with domination by one or more subsets. Characterization of TCR gene rearrangements in RadLV-induced lymphomas shows that most of these tumors are clonal or oligoclonal with respect to the J beta 2 TCR gene, while the J beta 1 TCR gene is rearranged in a minority (4 of 11) of lymphomas. TCR V beta repertoire analysis of 12 tumors reveals that 6 (50%) express exclusively the V beta 6 gene product, 2 (17%) are V beta 5+, and 1 (8%) each are V beta 8+ and V beta 9+. In normal C57BL/Ka mice, V beta 6 is expressed on 12%, V beta 5 is expressed on 9%, V beta 8 is expressed on 22%, and V beta 9 is expressed on 4% of TCRhi thymocytes. Thus, it appears that RadLV-induced thymic lymphomas are not randomly selected with respect to expressed TCR V beta type.

Animals↗
PubMed1999

Distinct roles of prostaglandin H synthases 1 and 2 in T-cell development.

Prostaglandin G and H synthases, or cyclooxygenases (COXs), catalyze the formation of prostaglandins (PGs). Whereas COX-1 is diffusely expressed in lymphoid cells in embryonic day 15.5 thymus, COX-2 expression is sparse, apparently limited to stromal cells. By contrast, COX-2 is predominant in a subset of medullary stromal cells in three- to five-week-old mice. The isozymes also differ in their contributions to lymphocyte development. Thus, experiments with selective COX-1 inhibitors in thymic lobes from normal and recombinase-activating gene-1 knockout mice support a role for this isoform in the transition from CD4(-)CD8(-) double-negative (DN) to CD4(+)CD8(+) double-positive (DP). Concordant data were obtained in COX-1 knockouts. Pharmacological inhibition and genetic deletion of COX-2, by contrast, support its role during early thymocyte proliferation and differentiation and, later, during maturation of the CD4 helper T-cell lineage. PGE2, but not other PGs, can rescue the effects of inhibition of either isoform, although it acts through distinct EP receptor subtypes. COX-dependent PG generation may represent a mechanism of thymic stromal support for T-cell development.

Animals↗
PubMed2004

In situ transduction of stromal cells and thymocytes upon intrathymic injection of lentiviral vectors.

BACKGROUND: The thymus is the primary site for T-cell development and induction of self-tolerance. Previous approaches towards manipulation of T-cell differentiation have used intrathymic injection of antigens, as proteins, cells or adenoviruses, leading to transient expression of the foreign protein. Lentiviral vectors, due to their unique ability to integrate into the genome of quiescent cells, may be best suited for long-term expression of a transgene in the thymus. RESULTS: Young adult mice were injected in the thymus with lentiviral vectors expressing eGFP or the hemaglutinin of the Influenza virus under the control of the ubiquitous phospho glycerate kinase promoter. Thymi were examined 5 to 90 days thereafter directly under a UV-light microscope and by flow cytometry. Intrathymic injection of lentiviral vectors predominantly results in infection of stromal cells that could be detected for at least 3 months. Importantly, hemaglutinin expression by thymic stromal cells mediated negative selection of thymocytes expressing the cognate T-cell receptor. In addition and despite the low multiplicity of infection, transduced thymocytes were also detected, even 30 days after injection. CONCLUSIONS: Our results demonstrate that intrathymic delivery of a lentiviral vector is an efficient means for stable expression of a foreign gene in the thymus. This new method of gene delivery may prove useful for induction of tolerance to a specific antigen and for gene therapy of severe combined immunodeficiencies.

Animals↗
PubMed1987

Selective expression of cholera toxin-receptor in rat medullary thymocytes.

Cholera toxin binding sites in frozen sections of rat thymus were studied by indirect immunofluorescence and were found to be localized selectively in the medulla of thymic lobules. By flow cytometric analysis, two populations of thymocytes differing in size and reactivity towards cholera toxin were detected; the small thymocytes comprising 15% of the total thymocytes were found to express the receptor. The two kinds of cells isolated were not however, distinctly different in morphology. But ganglioside GM1, the cholera toxin binding site in the small thymocytes, when quantified by TLC-immunostaining, was contained at a higher concentration than in the large thymocytes. These results indicate that GM1 should be a useful marker for analysis of thymocyte differentiation, and that cholera toxin-mediated thymocyte proliferation might only occur in the small medullary thymocytes.

Animals↗
PubMed2004

The expression of HLA-DO (H2-O) in B lymphocytes.

HLA-DO (H2-O in mice) is a nonpolymorphic transmembrane alphabeta heterodimer encoded in the class II region of the major histocompatibility complex (MHC). It is expressed selectively in B lymphocytes and thymic medullary epithelial cells. DO forms a stable complex with the peptide-loading catalyst HLA-DM in the endoplasmic reticulum (ER); in the absence of DM, DO is unstable. During intracellular transport and distribution in the endosomal compartments, the ratio of DO to DM changes. In primary B cells, only approx 50% of DM molecules are associated with DO. DO appears to regulate the peptide-loading function of DM in the MHC class II antigen-presentation pathway. Although certain discrepancies are present, results from most studies indicate that DO (as well as H2-O) inhibits DM (H2-M) function; this inhibition is pH-dependent. As a consequence, DO restrains presentation of exogenous antigens delivered through nonreceptor-mediated mechanisms; in addition, DO alters the peptide repertoire that is associated with cell-surface class II molecules. The biological function of DO remains obscure, partially because of the lack of striking phenotypes in the H2-O knockout mice. Results from recent studies indicate that DO expression in B cells is dynamic, and highly regulated during B-cell development and B-cell activation, suggesting that the physiological role of DO is to tailor the antigen presentation function of the B-lineage cells to meet their primary function at each stage of B-cell development and maturation. Further investigations are needed in this direction.

Animals↗