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Bruno Kyewski

Publications and source records attributed to Bruno Kyewski.

11 recordsLinked to original sources
PubMed2005

Expression of a natural tumor antigen by thymic epithelial cells impairs the tumor-protective CD4+ T-cell repertoire.

A variety of antigens that display a highly tissue-specific expression pattern have recently found to be also expressed in medullary thymic epithelial cells (mTEC). This unique feature of mTEC plays an important role in preventing hazardous autoimmune responses through thymic tolerization of T-cell subsets directed against autoantigens but could also limit the possibility of exploiting tumor-associated antigens for immune-mediated targeting of cancers. Our present study shows that expression of carcinoembryonic antigen (CEA) in thymic epithelial cells of CEA-transgenic mice results in tolerization of a major fraction of the CD4+ T-cell repertoire against this antigen, thereby markedly limiting the effect of CEA-specific immunization against CEA-overexpressing tumors. The expression of CEA in mTEC of CEA-transgenic mice is mirrored by its expression in human mTEC, arguing that promiscuous gene expression in these thymic stromal cells needs to be considered as a potential hurdle for immunotherapies of cancer that target tissue-specific autoantigens.

Amino Acid Sequence↗
PubMed2005

Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels.

The role of central tolerance induction has recently been revised after the discovery of promiscuous expression of tissue-restricted self-antigens in the thymus. The extent of tissue representation afforded by this mechanism and its cellular and molecular regulation are barely defined. Here we show that medullary thymic epithelial cells (mTECs) are specialized to express a highly diverse set of genes representing essentially all tissues of the body. Most, but not all, of these genes are induced in functionally mature CD80(hi) mTECs. Although the autoimmune regulator (Aire) is responsible for inducing a large portion of this gene pool, numerous tissue-restricted genes are also up-regulated in mature mTECs in the absence of Aire. Promiscuously expressed genes tend to colocalize in clusters in the genome. Analysis of a particular gene locus revealed expression of clustered genes to be contiguous within such a cluster and to encompass both Aire-dependent and -independent genes. A role for epigenetic regulation is furthermore implied by the selective loss of imprinting of the insulin-like growth factor 2 gene in mTECs. Our data document a remarkable cellular and molecular specialization of the thymic stroma in order to mimic the transcriptome of multiple peripheral tissues and, thus, maximize the scope of central self-tolerance.

Animals↗
PubMed2005

Linking signalling pathways, thymic stroma integrity and autoimmunity.

Medullary thymic epithelial cells (mTECs) are indispensable for self-tolerance to peripheral organs by virtue of their expression of a host of tissue-restricted self-antigens. The full extent of this promiscuous gene expression is confined to functionally mature mTECs. Consequently, any interference with signalling pathways directing the differentiation and/or proliferation of this mature subset will affect the scope of central tolerance and potentially predispose to autoimmunity. In a recent study, tumour necrosis factor receptor-associated factor 6 (TRAF6) has been identified as an essential component of a new signalling pathway directing mTEC development.

Animals↗
PubMed2004

Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters.

Promiscuous expression of tissue-specific self-antigens in the thymus imposes T cell tolerance and protects from autoimmune diseases, as shown in animal studies. Analysis of promiscuous gene expression in purified stromal cells of the human thymus at the single and global gene level documents the species conservation of this phenomenon. Medullary thymic epithelial cells overexpress a highly diverse set of genes (>400) including many tissue-specific antigens, disease-associated autoantigens, and cancer-germline genes. Although there are no apparent structural or functional commonalities among these genes and their products, they cluster along chromosomes. These findings have implications for human autoimmune diseases, immuno-therapy of tumors, and the understanding of the nature of this unorthodox regulation of gene expression.

Animals↗
PubMed2004

CREB function is required for normal thymic cellularity and post-irradiation recovery.

Recent generation of genetically modified Creb1 mutant mice has revealed an important role for CREB (cAMP responsive element binding protein) and the related proteins CREM (cAMP responsive element modulator) and ATF1 (activating transcription factor 1) in cell survival, in agreement with previous studies using overexpression of dominant-negative CREB (dnCREB). CREB and ATF1 are abundantly expressed in T cells and are rapidly activated by phosphorylation when T cells are stimulated through the T cell antigen receptor. We show that T cell-specific loss of CREB in mice, in combination with the loss of ATF1, results in reduced thymic cellularity and delayed thymic recovery following sublethal irradiation but no changes in T cell development or activation. These data show that loss of CREB function has specific effects on thymic T lymphocyte proliferation and homeostasis in vivo.

Activating Transcription Factor 1↗
PubMed2004

Regulating self-tolerance by deregulating gene expression.

Intrathymic expression of peripheral auto-antigens, termed promiscuous gene expression, extends the scope of central T-cell tolerance to peripheral organs and proves essential for the induction and maintenance of self-tolerance. The purification of antigen-presenting cells has been instrumental in identifying promiscuous gene expression as an inherent property of medullary epithelial cells. The pool of promiscuously expressed genes might encompass up to 10% of the whole genome. The remarkable diversity of this gene pool implies a complex mode of regulation, which cannot be solely explained by the action of a single factor, such as the transcriptional autoimmune regulator AIRE. Co-localization of promiscuously expressed genes in clusters also suggests epigenetic mechanisms (e.g. DNA methylation) to account for this unorthodox gene expression pattern. The identification of the molecular components controlling the expression of tissue-restricted genes in the thymus promises to add valuable new insights into the complex genetic regulation underlying most autoimmune diseases.

Animals↗
PubMed2004

Self-representation in the thymus: an extended view.

The thymus has been viewed as the main site of tolerance induction to self-antigens that are specifically expressed by thymic cells and abundant blood-borne self-antigens, whereas tolerance to tissue-restricted self-antigens has been ascribed to extrathymic (peripheral) tolerance mechanisms. However, the phenomenon of promiscuous expression of tissue-restricted self-antigens by medullary thymic epithelial cells has led to a reassessment of the role of central T-cell tolerance in preventing organ-specific autoimmunity. Recent evidence indicates that both genetic and epigenetic mechanisms account for this unorthodox mode of gene expression. As we discuss here, these new insights have implications for our understanding of self-tolerance in humans, its breakdown in autoimmune diseases and the significance of this tolerance mode in vertebrate evolution.

Animals↗
PubMed2004

Bone marrow microenvironment facilitating dendritic cell: CD4 T cell interactions and maintenance of CD4 memory.

This study shows that bone marrow (BM) stroma expresses constitutively multiple adhesion molecules (ICAM-1, VCAM-1, MadCAM-1, P-selectin) relevant for the homing and infiltration of BM by blood derived T lymphocytes, and also the co-stimulatory molecule CD80, relevant for T cell activation. T cells were capable of homing to BM but not to thymus. Homing to BM involved the integrins LFA-1alpha and alpha4 which interact with the above constitutively expressed cell adhesion molecules (CAMs). CD3 T cells were detected together with BM resident CD11c dendritic cells (DCs), often enriched in follicle-like structures in BM parenchyma. Cognate interactions between transferred antigen specific transgenic CD4 T cells and antigen laden BM-DCs led to formation of multicellular clusters in situ in BM, to generation of lymphoblasts and to clonal T cell expansion within such clusters. The great majority of BM-CD4 T cells had a memory phenotype suggesting that the BM microenvironment facilitates maintenance of CD4 memory. These results extend and corroborate our previous findings on BM-CD8 T cell mediated immune responses. Together these findings suggest that DC-T cell interactions in BM play an important role in immune responses to blood-borne antigen and in the establishment of systemic immunity and long-term memory.

Animals↗
PubMed2003

Bone marrow as a priming site for T-cell responses to blood-borne antigen.

Although bone marrow is known as a primary lymphoid organ, its potential to serve as a secondary immune organ has hardly been explored. Here we demonstrate that naive, antigen-specific T cells home to bone marrow, where they can be primed. Antigen presentation to T cells in bone marrow is mediated via resident CD11c+ dendritic cells. They are highly efficient in taking up exogenous blood-borne antigen and processing it via major histocompatibility complex class I and class II pathways. T-cell activation correlates with dendritic cell-T cell clustering in bone marrow stroma. Primary CD4+ and CD8+ T-cell responses generated in bone marrow occur in the absence of secondary lymphoid organs. The responses are not tolerogenic and result in generation of cytotoxic T cells, protective anti-tumor immunity and immunological memory. These findings highlight the uniqueness of bone marrow as an organ important for hemato- and lymphopoiesis and for systemic T cell-mediated immunity.

Animals↗
PubMed2003

Dynamic changes during the immune response in T cell-antigen-presenting cell clusters isolated from lymph nodes.

Activation of antigen-specific T cells by mature dendritic cells in secondary lymphoid organs is a key control point of the adaptive immune response. Here we describe the ex vivo isolation of preformed multicellular clusters between T cells and antigen-presenting cells. Adoptively transferred, antigen-specific T cells segregated into individual clusters where their activation and proliferation was initiated in vivo. Transit of the T cell cohort through the cluster compartment required 32-36 h. The precise timing of the response to agonistic epitopes was remarkably invariant regardless of the T cell lineage, the major histocompatibility complex haplotype, and the antigen dose. Interestingly, initiation of cell division of T cells specific for a subdominant epitope and a weak agonist was delayed by 6 h. The results provide a basis for the analysis of short range, mutual cell-cell interactions within such confined microenvironments.

Animals↗