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Results for “clonal deletion”

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PubMed2006

Severely impaired clonal deletion of CD4+ T cells in low-dose irradiated mice: role of T cell antigen receptor and IL-7 receptor signals.

Systemic administration of high doses of soluble Ag induces peripheral CD4+ T cell tolerance in unmanipulated hosts. To test whether tolerance is modified under conditions of transient lymphopenia, we tracked the response of 5C.C7 TCR-transgenic CD4+ T cells to i.v. moth cytochrome c peptide in mice that received low-dose gamma irradiation 10 days previously. This model was chosen because it does not support spontaneous lymphopenia-induced proliferation of 5C.C7 cells, allowing the study of Ag-specific responses without interference from simultaneous spontaneous proliferation. Clonal expansion in response to i.v. peptide was increased in irradiated mice, while clonal deletion was severely impaired in comparison with untreated animals. Amplified TCR triggering was observed in irradiated hosts, consistent with dendritic cell activation leading to enhanced Ag presentation. Failure of deletion was accompanied by persistent T cell activation and accumulation of Th1 effector cells. Up-regulated expression of IL-7R and the prosurvival protein Bcl-x(L) was associated with clonal persistence. Cells with memory and naive phenotypes were both represented within persistent clones, but no Th1 function could be demonstrated within the long-term memory population. Failure of clonal deletion in irradiated hosts represents a novel mechanism limiting TCR diversity in a lymphopenic environment and may contribute to subsequent autoimmunity.

Animals↗

PubMed1995

T cell repertoire and clonal deletion of Mtv superantigen-reactive T cells in mice lacking CD4 and CD8 molecules.

CD4-CD8- double-negative T cells constitute a lymphocyte subpopulation within the thymus and peripheral lymphatic organs that express a unique T cell receptor (TCR) repertoire and do not undergo negative selection. To test whether these cells develop as a distinct lineage or due to altered selection in the absence of CD4 and CD8 expression, we analyzed the TCR repertoire in mice lacking both CD4 and CD8 accessory molecules after homologous recombination (CD40/0CD80/0). We show that mature T cells of CD40/0CD80/0 mice express an unbiased diverse TCR V beta repertoire comparable to wild type mice. In addition, clonal deletion of mouse mammary tumor virus superantigen-reactive T cells did occur in CD40/0CD80/0 mice. These data show that the intrinsic lack of CD4 and CD8 expression has no effect on the mature TCR repertoire and that clonal deletion of superantigen-reactive cells is independent of CD4 and CD8 co-receptors.

Animals↗

PubMed2001

Aged mice exhibit in vivo defective peripheral clonal deletion of D(b)/H-Y reactive CD8(+) T cells.

We previously reported that T cells from aged mice were resistant to activation-induced cell death (AICD) in vitro. To determine whether the presence of AICD-resistant T cells is associated with defects in age-related peripheral clonal deletion in vivo, congenic male SCID mice were reconstituted with T cells from aged or young female D(b)/H-Y TCR (Tg71) transgenic mice. Compared with recipients of young cells, the recipients of T cells from aged mice exhibited a 3-fold increase in the percentage of autoreactive CD8(+) H-Y antigen-reactive T cells as defined by the clonotypic antibody, M33. There were significantly increased sera levels of interferon-gamma, a significantly decreased expression of FasL by M33(+)CD8(+) T cells, and significantly decreased apoptosis by DNA fragmentation staining of the spleen of mice reconstituted with T cells from aged mice compared to those from young mice. By day 21, the recipients of T cells from aged mice but not young mice, exhibited infiltration of CD3(+) cells into the non-lymphoid organs. These results indicate that there is defective peripheral deletion of the self-reactive T cells derived from aged female Tg71 mice, and that failure to delete these cells is associated with the defective T-cell clonal deletion in the recipient mice.

Adoptive Transfer↗

PubMed2002

Immune tolerance to combined organ and bone marrow transplants after fractionated lymphoid irradiation involves regulatory NK T cells and clonal deletion.

Immune tolerance to organ transplants has been reported in laboratory animals and in humans after nonmyeloablative conditioning of the host and infusion of donor bone marrow cells. We examined the mechanisms of immune tolerance to mouse cardiac allografts in MHC-mismatched hosts that developed mixed chimerism after posttransplant conditioning with a 2-wk course of multiple doses of lymphoid tissue irradiation, depletive anti-T cell Abs, and an infusion of donor bone marrow cells. When CD1(-/-) or J(alpha)281(-/-) hosts with markedly reduced NK T cells were used instead of wild-type hosts, then the conditioning regimen failed to induce tolerance to the heart allografts despite the development of mixed chimerism. Tolerance could be restored to the CD1(-/-) hosts by infusing enriched T cells from the bone marrow of wild-type mice containing CD1-reactive T cells but not from CD1(-/-) host-type mice. Tolerance could not be induced in either IL-4(-/-) or IL-10(-/-) hosts given the regimen despite the development of chimerism and clonal deletion of host T cells to donor MHC-Ags in the IL-10(-/-) hosts. We conclude that immune tolerance to bone marrow transplants involves clonal deletion, and tolerance to heart allografts in this model also involves regulatory CD1-reactive NK T cells.

Animals↗

PubMed1993

Clonal deletion of thymic mature T cells induced by staphylococcal enterotoxin B in murine fetal thymus organ culture.

The present study aims at investigating the intrathymic maturational stage of T cells at which clonal deletion can be induced. Staphylococcal enterotoxin B (SEB) was added to organ cultures of murine fetal thymus lobes at various time points of culture, and V beta 8-expressing cells were assayed on day 14. V beta 8 low-expressing (V beta 8lo) cells were reduced to 40-60% of the control receiving no SEB, though the reduction was ambiguous when SEB was given on day 13. In marked contrast, V beta 8 high-expressing (V beta 8hi) cells were virtually completely deleted in all groups including the group given SEB on day 13. Most of the V beta 8hi cells that were deleted by 24 h of treatment with SEB were shown to be of the CD4+8- mature phenotype, though CD4-8+V beta 8hi cells were also deleted. It was further shown that the thymic V beta 8hi CD4+8- cells recovered from organs cultured for 14 days without SEB responded to immobilized anti-V beta 8 monoclonal antibody, indicating that V beta 8hi cells, which were highly sensitive to clonal deletion, were functionally competent mature T cells. These results strongly suggest that the thymus is capable of eliminating all T cells recognizing antigen present in the thymus regardless of the maturational stage of T cells.

Animals↗

PubMed2005

Efficacy of clonal deletion vs. anergy of self-reactive CD4 T-cells for the prevention and reversal of autoimmune diabetes.

The self-reactive CD4 T-cells play an essential role in triggering and sustaining organ-specific autoimmune diseases. Silencing or elimination of these cells can prevent and reverse an autoimmune process. We have previously showed that a single dose-administration of a soluble dimeric MHC II-peptide chimera (DEF) in double-transgenic mice delayed the onset autoimmune diabetes, and restored the euglycemia in already diabetic mice for a period of 1 week. DEF dimer protection relied on induction of anergy of diabetogenic CD4 T-cells in spleen, and stimulation of IL-10-secreting T regulatory type 1 cells in pancreas. Herein, we show that an octameric form of DEF has doubled the period of protection and reversal of disease by clonal deletion of diabetogenic CD4 T-cells in both the thymic and peripheral compartments. Deletion occurred by activation-induced cell death subsequent to repartitioning and signaling of FAS-FADD apoptotic module in the plasma membrane lipid rafts. Our previous and present data indicated first, that DEF valence translates into various effects on the antigen-specific CD4 T-cells, i.e., Th2 immune deviation, anergy, and apoptosis. Second, the present findings argue for a better efficacy of clonal deletion than anergy of diabetogenic CD4 T-cells for the protection and reversal of autoimmune diabetes.

Animals↗

PubMed1991

Requirement of dendritic cells and B cells in the clonal deletion of Mls-reactive T cells in the thymus.

The present study was performed to identify cells responsible for the elimination of T cells reactive with minor lymphocyte-stimulating (Mls) antigens during T cell development. Experiments were carried out in a fetal thymus organ culture (FTOC) system. To examine the tolerance-inducing activity, various populations of cells from adult CBA/J (Mls-1a) mice were injected into deoxyguanosine (dGuo)-treated FTOC of C3H/He (Mls-1b) mice with a microinjector, and 2 d later, the thymus lobes were injected with fetal thymus cells from C3H/He mice as T cell precursors. After 14 d of cultivation, cells were harvested and assayed for the expression of the T cell receptor V beta 6 element. The absence or marked reduction of T cells expressing V beta 6 at high levels (V beta 6high) was regarded as indicating the deletion of Mls-1a-reactive T cells. T cell-depleted populations of thymic as well as splenic cells from CBA/J mice were able to induce clonal deletion. Further characterization of the effector cells was carried out by fractionating the spleen cells before injecting them into dGuo-FTOC. None of the dish-adherent population, dish-nonadherent population, or purified B cells alone were able to induce clonal deletion, whereas the addition of purified B cells to adherent cells restored tolerance inducibility. It was further shown that a combination of CBA/J B cells and C3H/He dendritic cells was effective in eliminating Mls-reactive clones. These results indicate that for the deletion of clones reactive with Mls antigens during T cell development in the thymus, both DC and B cells are required.

Animals↗

PubMed1993

Control of clonal deletion in the thymus: implications for tolerance induction.

Tolerance to foreign antigen by means of clonal deletion in the thymus can be achieved during embryonic or neonatal life, but not easily in the adult animal. It is concluded here that an immunological control by mature T cells prevents newly acquired antigen from being permanently deposited in the adult thymus. In this way, the originally established thymic antigen discrimination can be maintained successfully. Breakdown of the control circuit should permit tolerance induction even in the adult thymus.

Animals↗

PubMed1998

Cellular basis of long-term organ transplant acceptance: pivotal role of intrathymic clonal deletion and thymic dependence of bone marrow microchimerism-associated tolerance.

Long-term acceptance of MHC-incompatible organ allografts without chronic immunosuppressive therapy has been achieved in experimental animals. There are also reports, mainly in liver transplant, of patients who after complete withdrawal of immunosuppressants still have a functioning graft. It has been proposed that organ transplant implies a migratory flux of donor "passenger" leukocytes out of the graft into the recipient tissues or organs, serving to establish a persistent condition of "microchimerism," and being a tolerogenic precursor of chimeric cells. Although there is evidence that the same migratory mechanisms apply to all organ grafts, migration of passenger leukocytes is less in organs other than the liver, such as the kidney and heart. To enhance the acceptance of organs less tolerogenic than the liver, perioperative infusion of donor bone marrow has been attempted to increase the migration of donor leukocytes of bone marrow origin. It has been suggested that such peripheral donor microchimerism is not only associated with long-term acceptance of the organ graft but that it plays an active role in induction and maintenance of unresponsiveness. However, the intimate mechanisms(s) responsible for prolonged organ survival in this setting remains speculative. Experimental evidence that the thymus plays the major role in the development of self-tolerance and is also critical in the induction of acquired tolerance to exogenous antigens has focussed the attention on the intrathymic events that lead to donor-specific unresponsiveness to allograft. Data are available showing that after direct intrathymic injection of donor cells, clonal deletion of maturing host thymocytes occurs and is the major mechanism in the induction of donor-specific tolerance. The central role of the thymus in transplant tolerance is also supported by more recent findings that in mixed allogeneic bone marrow chimeras in mice with a nonmyeloablative conditioning regimen, migration of donor bone marrow-derived dendritic cells to the thymus serves to negatively select newly developing host T cells. Therefore, the peripheral T-cell component would be devoid of alloreactive population. Thus, lifelong intrathymic clonal deletion is the only significant mechanism involved in the maintenance of donor-specific T-cell tolerance that would allow the subsequent vascularized organ from the same donor to survive indefinitely.

Animals↗

PubMed1990

Clonal deletion: a mechanism of tolerance in mixed bone marrow chimeras.

The mechanism of antigen-specific immunologic unresponsiveness which results from lethal irradiation and mixed (syngeneic-allogeneic) bone marrow cell (BMC) reconstitution is unknown. To determine whether clonal deletion is the mechanism of tolerance in this model, monoclonal antibody (Mab) RR-4-4, specific for a T-cell receptor (V beta 6) reactive against the minor alloantigen MLsa, was employed. Six-week-old B10 mice (H-2b, Mlsb, Thyl.2) were tolerized to AKR antigens (H-2k, Mlsa, Thyl.1) by whole body irradiation (950 R) and iv infusion of T-cell-depleted (TCD) B10 BMC + non-TCD AKR BMC. Chimerism and antigen-specific tolerance were documented by flow microfluorometry (FMF), skin grafting, mixed lymphocyte reaction, and cell-mediated lympholysis. When tolerant B10 mice (n = 15) had accepted AKR skin grafts for greater than 100 days, these animals were studied for the presence of host V beta 6+ T cells using Mab RR-4-4. FMF revealed that 0-5% of host (B10) lymph node and spleen cells from chimeras were V beta 6+ while 15-20% of lymph node and spleen cells from control B10 mice expressed V beta 6. These data demonstrate that clonal deletion occurs in the lethal irradiation-mixed reconstitution model as evidenced by the near total elimination of Mlsa-reactive V beta 6+ T cells and suggest that it maybe a mechanism responsible for tolerance in adult mice.

Animals↗

PubMed1991

Relationship of cyclosporine A-mediated inhibition of clonal deletion and development of syngeneic graft-versus-host disease.

We have described a strain-specific graft-vs-host disease (GVHD)-like syndrome in syngeneic mouse radiation chimeras that developed in two of seven strains tested after cyclosporine A (CsA) therapy. It has been suggested, recently, that autoreactive T cells that develop as a result of CsA treatment may result from inhibition of clonal deletion and could be responsible for the development of this disease. To test this hypothesis, TCR expression, as a measure of tolerance induction, was analyzed in a series of syngeneic radiation chimeras (inducible and noninducible for syngeneic GVHD), with and without CsA treatment. Clonal deletion, as assessed by anti-TCR V beta chain mAb, appeared to occur normally in strains of mice inducible for syngeneic GVHD. Conversely, animals in which T cells bearing self-reactive TCR could be detected, did not develop the disease. This discrepancy did not appear to be due to a generalized difference in the effects of CsA on the various strains of mice used, as the effects of the drug (i.e., decreased mitogen responsiveness, inhibition of thymocyte maturation, etc.) appeared similar in all strains tested. Therefore, the development of CsA-induced autoreactive T cells as assessed by V beta TCR expression showed strain variation that did not correlate with the induction of syngeneic GVHD and suggested that other mechanisms may be involved in the development of this autoimmune phenomenon.

Animals↗

PubMed1994

Differential patterns of T cell clonal deletion in neonatal H-2 tolerance and I-E/Mls induced self-tolerance.

The pattern of clonal deletion of putative I-E-reactive (V beta 11) and Mls-reactive (V beta 3) T cells was evaluated and compared by cytofluorographic and immunohistochemical methods in a model of neonatal H-2 tolerance and in I-E- or Mls-bearing strains of mice which normally delete these cell populations (self-tolerance). The ontogeny of deletion of V beta 11+ cells was studied by evaluating thymic changes from birth until maturity in B10.S (H-2s/I-E-), B10.A (H-2k/d/I-E+) and B10.S mice intravenously infused at birth with (B10.SxB10.A)F1 lymphohaematopoietic cells. The reduction in V beta 11+ cells was most prevalent in the medullary region of the naive B10.A and neonatally injected B10.S animals and was corroborated by flow cytometry which demonstrated a marked reduction in single CD4 and CD8 positive B beta 11 T cells when compared to naive B10.S mice. However, immunohistochemistry illustrated that 'deletion' was never complete since V beta 11+ cells remained in the thymic cortex and splenic lymphoid follicles. By comparison, DBA/2 mice (Mlsc+ and previously documented to have decreased levels of V beta 3+ cells) showed a different pattern of deletion of V beta 3+ T cells than what was found for T cells bearing V beta 11 in animals deleting this population. DBA/2 thymi contained fewer thymic V beta 3- cells and there was more complete elimination of these cells, particularly in the periphery, by flow cytometry and immunohistology. The mice which do not delete V beta 3 cells (Mlsc-) showed that the majority of V beta 3- cells were located in the medulla with a few cells distributed in the cortical region. This pattern was notably different than the distribution of V beta 11 cells in thymi. Despite their location by histology, the majority of remaining V beta 3+ cells were dual CD4/CD8 positive (CD4+CD8+) by flow cytometric analysis. Our data illustrate that V beta 11 and V beta 3 T cells appear to be eliminated (i.e. 'deleted') at similar stages of maturation (single positive) during self-tolerance as well as in a neonatal H-2 tolerance model. However, the degree of elimination and the location of the cells remaining in these mice is dramatically different, depending on which T cell population is being evaluated and which deleting ligand is presented intrathymically. Thus, the accepted tenet of dual CD4+CD8+ cells localizing to the thymic cortex appears to have exceptions.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1991

T-cell maturation and clonal deletion in cyclosporine-induced autoimmunity.

In some circumstances cyclosporine (CyA) induces autoimmune phenomena, and a lethal form of syngeneic graft-vs-host disease (SGVHD) can be induced in rats by the administration of CyA. Although several rat strains develop this disease, in this study, we report that of six mouse strains tested, only the DBA/2 strain developed SGVHD. A comparison of the effect of CyA on thymocytic and peripheral T-cell populations revealed that CyA-induced alterations were similar in the two species, although more marked in rats. Notably, CyA-treated syngeneic bone marrow chimeras (SBMC) had transiently increased numbers of peripheral CD4+ CD8+ T-cells, expressing a marker normally limited to thymocytes. Examination of T-cell receptor (TCR) V beta expression in CyA-treated mice revealed a normal pattern of clonal deletion in all strains (including disease-prone DBA/2 mice), suggesting that CyA may induce autoimmunity without blocking intrathymic clonal deletion.

Animals↗

PubMed1992

Cyclosporine A and peripheral tolerance. Inhibition of veto cell-mediated clonal deletion of postthymic precursor cytotoxic T lymphocytes.

Veto cell-mediated suppression of CTL responses has been proposed as one mechanism by which self tolerance is maintained in mature T cell populations. We have reported that murine bone marrow cells cultured in the presence of high-dose IL-2 (activated bone marrow cells) mediate strong veto suppressor function in vitro and in vivo, and that such veto activity is effected through clonal deletion of cytotoxic T cell precursors. In our studies, we have determined that bone marrow cell populations from athymic NCr-nu mice (H-2d) mediate strong veto cell activity without exposure to exogenous IL-2 in vitro. To examine mechanisms by which these naturally occurring veto cell populations in BM suppress precursor CTL (pCTL) responses, we used as a responding cell population in MLC, spleen cells of transgenic mice expressing at high frequency TCR specific for H-2 Ld encoded Ag with stimulation by H-2d-expressing cells in culture. Flow cytometric analysis was performed by staining the responding MLC cell population with the mAb 1B2 specific for the transgene-encoded TCR and determined changes of 1B2+ T cells. Such experiments demonstrated that the anti-H-2d cytotoxic response by these cell populations was specifically suppressed by NCr-nu (H-2d) bone marrow, and that 1B2+ pCTL were in fact specifically deleted from the responding cell population by incubation with such naturally occurring veto cell populations expressing the appropriate target Ag. In addition, to further understand the interactions of pCTL and veto cells and possible contributions by the latter to peripheral tolerance, we evaluated the effect of cyclosporine A (CsA) on veto cell-mediated suppression of pCTL of the transgenic mice. CsA inhibited veto cell-mediated suppression of cytotoxic T cell responses, and this inhibition correlated with a lack of clonal deletion of pCTL by veto cells in the presence of CsA. Furthermore, CsA exerted its effect through pCTL and not through veto cells, indicating that pCTL may play an active role in their own deletion by veto cells.

Animals↗

PubMed1993

CD28-B7 interactions are not required for intrathymic clonal deletion.

Activation of antigen specific T cells requires more than stimulation through the TCR-CD3 complex. A second or costimulatory signal is also required, and this second signal can be delivered by interactions between CD28 and B7, ligands expressed on T cells and antigen presenting cells respectively. We have examined the role of the CD28-B7 interaction in superantigen mediated T cell activation and intrathymic negative selection by blocking B7 molecules with a high affinity soluble ligand, CTLA4lg. In vitro T cell activation mediated by both virally encoded endogenous and exogenous bacterial superantigens was significantly blocked by the addition of CTL4Alg to cultures. However, intrathymic clonal deletion in vivo and in fetal thymic organ cultures was not inhibited by blocking B7 molecules. Therefore, although the CD28-B7 costimulation pathway is necessary for T cell activation, it does not appear to play a role in intrathymic clonal deletion.

Abatacept↗

PubMed1991

Clonal deletion and autoreactivity in extrathymic CD4-CD8-(double negative) T cell receptor-alpha/beta T cells.

Peripheral CD4-CD8- (double negative) T cells (DNT cells) that express TCR-alpha/beta (DNT-alpha/beta cells) are expanded in some autoimmunity-prone mice, but in normal mice these cells have not been extensively studied. In this study, we isolated splenic DNT-alpha/beta cells that are Thy-1+, Ly-1+, MAC-1-, J11d-, and Ia-. Only 5% of these cells were B220+. Freshly isolated DNT-alpha/beta cells did not proliferate in MLC; however, these cells responded strongly to stimulation with matrix-bound anti-TCR-alpha/beta antibodies or Con A. After activation the cells became CD4+CD8-, acquired high reactivity in both syngeneic and allogeneic MLC, but lacked cytotoxicity. After activation the cells gradually reverted to a double-negative phenotype in culture. Surprisingly, despite high autoreactivity the analysis of TCR V beta expression revealed a near normal pattern of Mls-1a- and I-E-induced clonal deletions. These findings reveal that DNT-alpha/beta cells are subject to negative selection and that autoreactivity cannot be attributed to a general failure of clonal deletion in this T cell subpopulation. DNT-alpha/beta cells may normally remain tolerant by down-regulating the CD4 molecule.

Animals↗

PubMed1994

Delay in expression of a mammary tumor provirus is responsible for defective clonal deletion during postnatal period.

A gene-encoding ligand for deletion of T cells bearing TcRV beta 6 and V beta 8.1 cosegregates a new mammary tumor provirus locus, Mtv-50 in NC mice. The sequence of the open reading frame (ORF) in the 3' long terminal repeat (LTR) of Mtv-50 was strikingly similar to those of Mtv-7, Mtv-43 and exogenous mouse mammary tumor virus (SW) with properties of minor lymphocyte stimulating antigen 1a. Consistent with previous reports, clonal deletion of mature thymocytes bearing TcRV beta 6 was defective during the early postnatal period of mice carrying Mtv-50. Appreciable levels of mRNA corresponding to common Mtv ORF and Mtv-6 ORF were expressed in the neonatal thymus, while little, if any, mRNA corresponding to Mtv-50 ORF was detected in the thymus at the early postnatal stage. Delay in expression of Mtv-50 ORF during the postnatal period may be responsible for the failure of clonal deletion of V beta 6-T cells in the early postnatal life of mice carrying Mtv-50.

Amino Acid Sequence↗

PubMed1983

Antigen-presenting cells from nonresponder strain 2 guinea pigs are fully competent to present bovine insulin B chain to responder strain 13 T cells. Evidence against a determinant selection model and in favor of a clonal deletion model of immune response gene function.

To test directly the determinant selection hypothesis of immune response gene function, we primed strain 13 T lymphocytes in vitro with allogeneic bovine insulin pulsed strain 2 macrophages. Strain 2 macrophages were found to be fully competent to present bovine insulin B chain to strain 13 T cells despite the fact that strain 2 guinea pigs are normally totally unresponsive to this antigen. These results are incompatible with a strict interpretation of the determinant selection hypothesis, which would have predicted that strain 2 macrophages would have been restricted to the presentation of A chain loop determinants. In addition, a comparison of the reactivity profiles of self-Ia- and allo-Ia-restricted strain 13 T cells to a series of synthetic B chain peptide fragments revealed that the allo-Ia-restricted populations could be activated by autologous guinea pig insulin. Taken together, these observations strongly suggest that the clonal deletion of self-reactive cells is likely to be I region restricted and that nonresponsiveness to any protein antigen may result from a restriction in the T cell repertoire that is generated during ontogeny by a clonal deletion mechanism of tolerance to self.

Animals↗