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N Auphan

Publications and source records attributed to N Auphan.

At least 19 recordsLinked to original sources
PubMed1999

Differential requirements for NF-kappaB and AP-1 trans-activation in response to minimal TCR engagement by a partial agonist in naive CD8 T cells.

We investigated the basis for partial reactivity of naive CD8 T cells expressing an alloreactive transgenic TCR in response to a mutant alloantigen. When unstimulated APCs were used, IFN-gamma as well as IL-2 and cell proliferation were observed in response to wild-type Ag, whereas mutant Ag induced only IFN-gamma. DNA binding and reporter gene assays showed that the response to mutant Ag involved NF-kappaB, but not AP-1 activation, whereas wild-type Ag activated both transcription factors. Increasing the contribution of costimulatory signals by using LPS-activated APCs partially corrected the activation by mutant Ag, because proliferation and weak IL-2 production could be measured. This also led to AP-1 activation, albeit with delayed kinetics, in response to mutant Ag. To explain how engagement of the same TCR by distinct ligands results in different T cell responses, it may be proposed, in line with models stressing the importance of the kinetics of Ag/TCR interaction, that two types of signals be distinguished: a "fast" short-lived signal is sufficient to activate NF-kappaB; whereas a "slow" signal obtained after prolonged TCR engagement is required for AP-1 activation. Failure to activate AP-1 in limiting conditions (unstimulated mutant APC) was partially corrected by increasing costimulation.

Animals↗
PubMed1998

Consequences of intrathymic TCR engagement by partial agonist on selection events and peripheral T cell activation program.

Functions elicited from mature T cells depend on the nature of the Ag. Thus, an agonist induces a larger set of cytokine responses than a partial agonist. Additionally, Ags present in the thymus influence both the selection of TCRs generated by gene rearrangement and the potential functional program of developing thymocytes. This can be approached by analysing the development of T cells in mice expressing the same transgenic TCR (tgTCR) under different conditions of intrathymic selection. H-2Kbm8 was found to act as a partial agonist for CD8+ T cells expressing a tgTCR specific for the H-2Kb alloantigen. Intrathymic exposure to full or to partial agonist affected the development of thymocytes at different stages, consistent with the respective CD8-independent and -dependent characteristic of the tgTCR/Ag interaction. The presence of the partial agonist led to the accumulation of a major population of thymocytes (tgTCR(high) CD4- CD8(low)) originating from TCR engagement at the immature single-positive CD8(low) stage as evidenced by: 1) results from reaggregated thymic organ culture in the presence of H-2(k/bm8) thymic stromal cells; 2) the absence of CD4+ thymocytes, the development of which depends on rearrangements of endogenous TCR alpha genes; and 3) the identification of the CD8(low) thymocytes as cycling cells. Peripheral CD8(low) T cells selected in an H-2(k/bm8) thymus expressed a partial functional program in response to H-2Kb, akin to the response of CD8(high) T cells to a partial agonist. The analysis of the molecular bases for partial reactivity revealed a correlation with inefficient AP-1, but efficient NF-kappaB transactivation.

Animals↗
PubMed1996

Multiplex messenger assay: simultaneous, quantitative measurement of expression of many genes in the context of T cell activation.

The hybridization signature approach, using colony filters and labeled complex probes, can provide high throughput measurement of gene activity. We describe here the implementation of this method to follow the expression levels of 47 genes in resting and activated T cells, as well as in epithelial cells. Using 4-fold spotting of colonies, imaging plate detection and various correction and normalization procedures, the technique is sensitive enough to quantify expression levels for sequences present at 0.005% abundance in the probe. Comparison with Northern blotting shows good consistency between the two methods. Upon activation of a T cell clone by an anti-CD3 antibody variations ranging from 2- to 20-fold are measured, some of which had not been reported previously. This 'multiplex messenger assay' method, performed using available commercial apparatus, can be used in many cases where simultaneous assessment of mRNA levels for many genes is of interest.

Animals↗
PubMed1996

Developmental control of antigen-induced thymic transcription factors.

Antigen engagement of the TCR may lead to activation of mature T cells while inducing deletion or positive selection of immature thymocytes. Using thymocytes from TCR transgenic mice recognizing the allo-antigen H-2Kb we investigated whether double-positive CD4+CD8+ (DP) thymocytes constitute a particular developmental stage where signals originating from surface receptor engagement will lead to distinct nuclear signaling. We show that the developmental control of transcription factors is apparent, at least at two levels. First, NF-AT binding activity was not induced in response to either antigen or phorbol myristate acetate (PMA)/lonomycin in DP thymocytes, whereas it was induced in single-positive CD8 thymocytes. Second, antigen induced a different pattern of transcription factor binding activities than PMA/lonomycin in DP thymocytes, AP-1 activity being selectively induced by antigen and NF-kappa B by PMA/lonomycin. Further we show that the transcription factors found to be induced in the DP thymic population were not susceptible to the inhibitory effect of cyclosporin A.

Animals↗
PubMed1995

Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis.

Glucocorticoids are among the most potent anti-inflammatory and immunosuppressive agents. They inhibit synthesis of almost all known cytokines and of several cell surface molecules required for immune function, but the mechanism underlying this activity has been unclear. Here it is shown that glucocorticoids are potent inhibitors of nuclear factor kappa B (NF-kappa B) activation in mice and cultured cells. This inhibition is mediated by induction of the I kappa B alpha inhibitory protein, which traps activated NF-kappa B in inactive cytoplasmic complexes. Because NF-kappa B activates many immunoregulatory genes in response to pro-inflammatory stimuli, the inhibition of its activity can be a major component of the anti-inflammatory activity of glucocorticoids.

Animals↗
PubMed1995

Glucocorticoid-induced apoptosis of human leukemic cells is caused by the repressive function of the glucocorticoid receptor.

Induction of apoptosis in lymphocytes, which may account for the therapeutic effects of glucocorticoids in various diseases including leukemia, depends on the glucocorticoid receptor. However, the events leading from the activated receptor to cell lysis are not understood. A prevailing hypothesis postulates induction of so-called 'lysis genes' by the activated receptor. In this study, we show that an activation-deficient glucocorticoid receptor mutant is as effective as the wild-type receptor in repression of AP-1 activity, inhibition of interleukin-2 production, inhibition of c-myc expression and induction of apoptosis. Furthermore, we show that retinoic acid can also induce apoptosis in these cells through the retinoic acid receptor, whose repressive functions but not target site specificity, are similar to those of the glucocorticoid receptor. Therefore, the primary effect of the receptor in glucocorticoid-mediated apoptosis correlates with transcriptional repression rather than activation and could be mediated by interference with other transcription factors required for cell survival.

Amino Acid Sequence↗
PubMed1995

Two signaling pathways can lead to Fas ligand expression in CD8+ cytotoxic T lymphocyte clones.

As shown previously, a given cytotoxic T lymphocyte (CTL) clone (KB5.C20) could be induced to express the Fas ligand (FasL) by either T cell receptor (TCR) engagement or phorbol 12-myristate 13-acetate (PMA)/ionomycin stimulation. In contrast, another CTL clone (BM3.3) has now been found to exert Fas-based cytotoxicity only after TCR engagement, but not after PMA/ionomycin stimulation. This suggested the existence of a PMA-insensitive, antigen-induced pathway leading to FasL expression. The inability of PMA to promote Fas-based cytotoxicity in BM3.3 cells was correlated with a defect in expression of the classical protein kinase C (PKC) isoforms alpha and beta I. In KB5.C20 cells depleted of PMA-sensitive PKC isoforms and thus no longer responsive to PMA, Fas-based cytotoxicity could still be induced via the TCR/CD3 pathway. On the other hand, a requirement for phosphatidylinositol-3 kinase (PI3K) selectively in this TCR/CD3-induced pathway was demonstrated by specific inhibition with wortmannin. These results suggest that FasL expression when induced via the TCR/CD3 involves PI3K, and when induced by PMA/ionomycin requires the expression of PMA-sensitive PKC isoforms absent in clone BM3.3. Additional data suggest that in neither case was NF-kappa B activation implicated in FasL expression.

Androstadienes↗
PubMed1994

Tolerance induction as a multi-step process.

Tolerant T cells are characterized by their partial or full resistance to activation by antigen. We investigated whether tolerant T cells were still receptive to further tolerogenic signals. T cells expressing a transgenic T cell receptor (TCR) specific for the major histocompatibility complex (MHC) class I molecule Kb were deleted in mice carrying Kb but not in mice expressing the mutant Kb-molecule Kbm1 [TCR (H-2bm1 x k) mice]. These T cells were tolerant in vivo but could be activated in vitro by the Kb antigen. This in vitro reactivity was abolished after the tolerant T cells encountered Kb-positive cells that had been intravenously injected. Furthermore, in TCR (H-2bm1 x k) mice expressing Kb only on hepatocytes, no T lymphocytes bearing the transgenic TCR could be found in the periphery, indicating that the additional contact with Kb on hepatocytes led to deletion of the tolerant T cells. These findings demonstrate that tolerance induction can be a multi-step process.

Animals↗
PubMed1994

The degree of CD8 dependence of cytolytic T cell precursors is determined by the nature of the T cell receptor (TCR) and influences negative selection in TCR-transgenic mice.

Although much has been learned about CD8 structure-function properties, it has so far not been tested whether the nature of the TCR is sufficient to transfer the property of CD8 dependence versus non-dependence to CD8+ cytotoxic T lymphocytes (CTL) and their precursors differentiating in T cell receptor (TCR)-transgenic (Tg) mice. In the present study, we compared the characteristics of dependence on CD8 for stimulation of CTL precursors and antigen-specific cytolysis by CD8+ T cells from two TCR-Tg mice expressing respectively the TCR (Tg) from a "CD8-dependent" and from a "CD8-independent" CTL clone, which were both reactive against the H-2Kb alloantigen and originated from H-2k mice. The results indicate that the property of the Tg+CD8+ cells from H-2k TCR-Tg mice corresponds to that of the CTL clone of origin, demonstrating that it is linked to the nature of the TCR. Consistent with this property, Tg+CD4+ cells could also differentiate into H-2Kb-specific CTL when originating from the "CD8-independent", but not from the "CD8-dependent" Tg-TCR. The influence of the property of "CD8 dependence" on negative selection occurring in TCR-Tg H-2k/b mice was apparent at two levels: (i) in the thymus, the extent of deletion was much more pronounced for the "CD8-independent" TCR-Tg mice; (ii) in the periphery, Tg+(hi) cells with low to negative CD8 expression were present for the "CD8-dependent" Tg-TCR, whereas only Tg+CD4-CD8- cells with low surface Tg-TCR and CD3 expression were found for the "CD8-independent" Tg-TCR, indicating that Tg+CD4-CD8- cells are susceptible to tolerance induction involving TCR/CD3 surface down-modulation. Furthermore, different in vitro conditions led to H-2Kb-induced stimulation of Tg+CD4-CD8- cells to differentiate into CTL detected in an anti-TCR clonotypic monoclonal antibody redirected cytolysis assay. Culture in interleukin-2 of H-2k/b Tg+CD4-CD8- cells was sufficient to induced CTL activity in the "CD8-independent" model, whereas stimulation with cells which overexpressed H-2Kb was required in addition to interleukin-2 to induce CTL differentiation in the "CD8-dependent" model. These data suggest that peripheral Tg+CD4-CD8- cells present in a situation of in vivo tolerance to H-2Kb can still be triggered by H-2Kb with a sensitivity correlated with the degree of CD8 dependence.

Animals↗
PubMed1994

Induction of tolerance to self MHC class I molecules expressed under the control of milk protein or beta-globin gene promoters.

We have studied tolerance induction in transgenic CBA mice expressing H-2Kb genes under the influence of guinea-pig alpha-lactalbumin (KAL) or human beta-globin gene promoter (K beta). KAL radio-resistant cells, but not bone marrow derived cells, induce tolerance to H-2Kb in chimeric mice. In contrast, bone marrow derived and radio-resistant cells of K beta mice induce tolerance. Although appropriate, tissue-specific, expression of H-2Kb molecules occurs in KAL and K beta mice, H-2Kb is expressed at low levels in thymus of transgenic mice. In addition, dendritic cells and macrophages express H-2Kb molecules when K beta, but not when KAL bone marrow is cultured in vitro. The mode of tolerance induction was examined in double transgenic mice by mating KAL or K beta mice to mice expressing TCR transgenes (Tg-TCR) derived from a H-2Kb specific, CD8-independent cytotoxic T cell clone. In both cases, a large number of Tg-TCR+ CD8+CD4+ thymocytes develop but mature CD8+CD4- thymocytes fail to appear suggesting that thymocytes are eliminated late in development. Some CD8-CD4- and CD8-CD4+ Tg-TCR+ T cells develop in double transgenic mice and respond to activation through their TCR-CD3 complex in vitro, although no responses to stimulation with H-2Kb expressing cells were detected. Thus, tolerance induction in KAL and K beta mice proceeds via a deletional mechanism that is inefficient due either to low numbers of H-2Kb expressing thymic cells or to the low levels of H-2Kb expressed by thymic cells, or to a combination of these factors.

Animals↗
PubMed1993

Distinct requirements of positive and negative selection for selecting cell type and CD8 interaction.

We investigated the requirements of positive and negative selection in the thymus for CD8 interaction and the selecting cell type. Thymic epithelial cells are known to mediate positive selection, whereas thymocytes fail to do so. The reason for this failure could be either the low amount of MHC class I molecules on thymocytes or the lack of other properties required for positive selection. To address this question a CD2.Kb transgenic mouse was prepared in which the expression of the Kb gene is under control of the CD2 promoter. In these mice the thymocytes exhibited very high levels of Kb. The mice were crossed with two TCR transgenic mice expressing either the Des.TCR (anti-Kb), which is positively selected on Kk and negatively on Kb, and the 2C.TCR (anti-Ld) with positive selection on Kb and negative on Ld. Despite the high Kb expression on thymocytes in CD2.Kb x 2C.TCR mice no positive selection was observed, whereas efficient negative selection was found in CD2.Kb x Des.TCR F1 mice. Thus, although thymocytes can negatively select, even a strong increase of MHC class I expression cannot convert them into positively selecting cells. This is consistent with the notion that thymic epithelium is specialized for positive selection, but the respective difference between thymocytes and thymic epithelium is not clear. The influence of CD8 was investigated using transgenic mice expressing a Kk/A2 or a Kb/A2 hybrid gene in which the promoter, the alpha 1, alpha 2 domains were of mouse origin and the alpha 3 domain of human origin. Because the murine CD8 molecule does not efficiently bind to human HLA class I, in these mice the CD8 interaction was impaired. In Kb/A2 x 2C.TCR and Kk/A2 x Des.TCR mice no positive selection of the respective TCR was found, whereas in Kb/A2 x Des.TCR mice negative selection was still functional. Altogether, the results indicate that positive selection depends more strictly on CD8 interaction and cell type than negative selection.

Animals↗
PubMed1992

Threshold tolerance in H-2Kb-specific TCR transgenic mice expressing mutant H-2Kb: conversion of helper-independent to helper-dependent CTL.

To evaluate the role of the structure of the class I molecule and associated peptide(s) in intrathymic selection and tolerance, mice expressing as a transgene (tg) a TCR specific for the H-2Kb alloantigen were crossed with mice expressing the mutant class I molecule H-2Kbm1 or H-2Kbm8. In H-2k/k TCR tg mice (in a situation of exclusive positive selection), peripheral tg TCR expressing (Ti+) CD8+ T cells showed high, suboptimal, and an absence of reactivity for H-2Kb, H-2Kbm1, and H-2Kbm8, respectively. In the peripheral lymphoid organs of TCR tg H-2k/k, H-2k/bm8, H-2k/bm1, and H-2k/b mice respectively, the tg TCR was expressed on T cells with decreasing intensity of surface CD8. Thymic subpopulations of TCR tg mice presented a pattern of negative selection with decreasing intensity from H-2k/b to H-2k/bm1 and H-2k/bm8. This suggests that a weak interaction between the TCR and H-2Kbm8 exists which partially results in negative, but not in positive, intrathymic selection. Results further indicate that expression of H-2Kbm8 does not induce tolerance to H-2Kb. In H-2k/bm1 mice, the peripheral Ti+ CD8lo cells express two distinct types of 'threshold' tolerance in vitro: (i) they generate cytotoxic T lymphocytes (CTL), in the presence of exogenous IL-2, which fail to respond to H-2Kbm1 but remain reactive to H-2Kb; and (ii) they do not make significant titers of IL-2 and do not significantly proliferate in response to H-2Kb, unlike the Ti+ CD8+ T cells from H-2k/k TCR tg mice which respond efficiently. These results show that tolerance is induced up to a level of non-reactivity within a given MHC environment: for the same TCR, CTL reactivity to H-2Kbm1 is totally lost, whereas CTL reactivity to H-2Kb is only slightly reduced. Additionally, proliferation and IL-2 production by Ti+ CD8+ cells in response to H-2Kb were strongly affected in H-2k/bm1 mice. Thus, in H-2k/k mice the Ti+ CD8+ cells behave as helper-independent, whereas in H-2k/bm1 mice CD8+ cells expressing the same TCR behave as helper-dependent CTL.

Animals↗
PubMed1992

Influence of antigen density on degree of clonal deletion in T cell receptor transgenic mice.

The extent of peripheral clonal deletion of the T cell antigen receptor (TCR) from a CD8-dependent cytotoxic T lymphocyte of H-2k origin with alloreactivity for H-2Kb was measured in a TCR transgenic (Tg) model by use of a clonotype-specific mAb (anti-Ti mAb). Deletion varied depending on whether the TCR Tg was expressed in mice heterozygous (H-2k x b) or homozygous (H-2b x b) for the H-2Kb antigen. CD8 surface staining and functional analyses of peripheral T cells stimulated with polyclonal activators in bulk culture or by limiting dilution confirmed that in the H-2b x b mice few Ti+ cells were generated as measured by anti-Ti mAb-dependent target cell killing; while such cells could readily be detected in the H-2k x b mice. The latter maintained non-responsiveness to H-2Kb, as measured by cytolysis of H-2Kb-expressing tumor target cells, due to their down-regulation of surface CD8 expression. The question of whether the difference between H-2b x b and H-2k x b mice was due to the influence of positive selection imposed by the k haplotype in the H-2k x b hybrid, or to the lower antigen density in heterozygous than homozygous mice was addressed by analysis of H-2b x d Tg mice, H-2d being a non-selecting haplotype. Results obtained were similar for H-2b x d and H-2k x b Tg mice, suggesting that the density of the H-2Kb antigen may be one of the parameters controlling the extent of clonal deletion in the thymus.

Animals↗
PubMed1991

Engineered secreted T-cell receptor alpha beta heterodimers.

We have produced a soluble form of a mouse alpha beta T-cell antigen receptor (TCR) by shuffling its variable (V) and constant (C) domains to the C region of an immunoglobulin kappa light chain. These chimeric molecules composed of V alpha C alpha C kappa and V beta C beta C kappa chains were efficiently secreted (up to 1 micrograms/ml) by transfected myeloma cells as noncovalent heterodimers of about 95-kDa molecular mass. In the absence of direct binding measurement, we have refined the epitopic analysis of the soluble V alpha C alpha C kappa-V beta C beta C kappa dimers and shown that they react with an anti-clonotypic antibody and two antibodies directed to the C domain of the TCR alpha and beta chains. Conversely, we have raised three distinct monoclonal antibodies against the soluble TCR heterodimers and shown that they recognize surface-expressed TCRs. Two of these antibodies were found to react specifically with the products of the V alpha 2 (V delta 8) and V beta 2 gene segments, respectively. When considered together, these data suggest that these soluble TCR molecules are folded in a conformation indistinguishable from that which they assume at the cell surface.

Amino Acid Sequence↗
PubMed1991

T cell receptor/CD3 complex internalization following activation of a cytolytic T cell clone: evidence for a protein kinase C-independent staurosporine-sensitive step.

The fate of the T cell receptor (TcR)/CD3 complex was examined on a cytotoxic T lymphocyte (CTL) clone (KB5.C20) activated either via binding of an anti-TcR monoclonal antibody (mAb) or by a Ca2+ ionophore and phorbol 12-myristate 13-acetate (PMA). After binding of the anti-TcR mAb, electron microscopy revealed internalization through coated vesicles followed by slow degradation of the antibody as shown by use of radiolabeled mAb. The influence of activation on TcR/CD3 internalization was analyzed. The Ca2+ ionophore alone had no effect on internalization, whereas PMA induced an accelerated internalization of anti-TcR mAb. PMA-induced internalization was dependent on protein kinase C (PKC) as shown by its absence in PKC-depleted cells or in the presence of the PKC inhibitor staurosporine. Anti-TcR mAb-induced internalization was maintained in PKC-depleted cells, but unexpectedly remained sensitive to inhibition by staurosporine. The monovalent anti-TcR mAb Fab fragment is non-stimulatory for the CTL. It was poorly internalized but its internalization was induced by PMA. Surprisingly, on PKC-depleted cells, the Fab was internalized more readily than in untreated cells and this internalization was sensitive to inhibition by staurosporine. Inhibition of PMA-induced phosphorylation of gamma and epsilon subunits of CD3 was demonstrated after depletion of PKC or in the presence of staurosporine, confirming that PKC function was inhibited in those conditions. Cross-linking of the TcR via plastic-coated anti-TcR mAb led to phosphorylation of CD3 gamma and epsilon and also of zeta, known to be phosphorylated on tyrosines. All of these phosphorylation events were inhibited by treatment with staurosporine. Our results indicate that staurosporine inhibits the receptor internalization induced by anti-TcR mAb by means other than inhibition of PKC, suggesting that other kinases may control a step of this internalization process.

Alkaloids↗
PubMed1991

Biochemical and functional association between CD8 and H-2 at the surface of a T cell clone.

In an attempt to define structures interacting with CD8 molecules during activation of CD8+ cells, immunoprecipitates of CD8 and Tcr-CD3 molecules from lysates of a surface-labeled CTL clone were analyzed. No proteins other than the known Tcr alpha/beta and associated CD3 components were detected in either anti-Tcr or anti-CD3 immunoprecipitates, whether or not the CTL clone had been activated. However, anti-CD8 antibodies co-precipitated class I MHC heavy chain and associated beta 2-microglobulin in all conditions. The latter co-precipitation was shown to result from "cis-type" interactions between CD8 and class I MHC proteins on the same cell and to involve a degree of selectivity, as class I MHC molecules were absent from immunoprecipitates of highly expressed cell surface molecules such as LFA-1. A further analysis of cell surface molecular distribution during antigen-dependent CTL-target cell interaction by double fluorescence-microscopy in non-activating conditions indicated that an increased density of CTL class I molecules was found in the CTL-target cell contact zone of most conjugates with redistributed CD8 molecules. A possible role for "cis-type" class I MHC-CD8 interactions in the dynamics of CTL-target cell contacts is proposed.

Animals↗
PubMed1991

Non-deletional mechanisms of peripheral and central tolerance: studies with transgenic mice with tissue-specific expression of a foreign MHC class I antigen.

The studies described here reveal a surprising variety of non-deletional manifestations of tolerance (anergy and unresponsiveness) in both the thymus and peripheral lymphoid organs. This can be observed in anti-Kb TCR transgenic mice crossed with normal Kb positive mice, and in TCR mice crossed with transgenic mice expressing Kb in restricted tissues, such as liver, epithelial cells, cells of neuroectodermal origin etc. Thymic induction of unresponsiveness: Transgenic mice were prepared with the a, beta TCR genes from a CD8-dependent and Kb-specific CTL clone. In homozygous H-2b mice clonotype+ cells were found in the thymus but none or few in the periphery, suggesting that deletion occurs in the thymus although lack of migration to the periphery has not been ruled out. In H-2 heterozygous mice (TCR.H-2kxb) deletion was incomplete in the thymus and clonotype+ cells accumulated substantially in the periphery. Most of them had downregulated their CD8 molecules. The clonotype+ cells in both the thymus and periphery were unresponsive to the Kb antigen in vitro, suggesting the induction of anergy in the thymus. The inefficient negative selection in H-hkxb heterozygous mice is probably due to the lower Kb expression in comparison to H-2b homozygous mice. We then further reduced the amount of Kb expression in the thymus by constructing Kb transgenic mice using the 0.8 Kb fragment of the keratin IV promoter. In the thymus expression was only observed on a subset of medullary epithelial cells. When these mice were crossed with the TCR transgenic mice than no deletion was observed in the thymus. However, the clonotype+ CD8+ thymocytes could not respond to Kb in vitro, indicating that they had been rendered anergic in the thymus. These data show that unresponsiveness can be induced in the thymus, that the extent of clonal deletion can vary greatly owing to a change in antigen expression by a factor of two as in H-2 heterozygous versus homozygous mice, and that expression of Kb on a few medullary thymic epithelial cells is sufficient to induce anergy. Peripheral induction of unresponsiveness: To study the consequence of tissue-specific tolerogen expression we have generated transgenic mice expressing Kb exclusively in cells of neuroectodermal origin (GFAP.Kb mice) in the liver (alumin.Kb mice), or in certain epithelial cells outside the thymus (2.4 keratin IV.Kb mice). Consistent with the absence of Kb expression in the thymus there was no deletion of clonotype+ CD8+ cells in the thymus, and the thymocytes were fully functional.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗