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Ludger Klein

Publications and source records attributed to Ludger Klein.

13 recordsLinked to original sources
PubMed2006

A central role for central tolerance.

Recent elucidation of the role of central tolerance in preventing organ-specific autoimmunity has changed our concepts of self/nonself discrimination. This paradigmatic shift is largely attributable to the discovery of promiscuous expression of tissue-restricted self-antigens (TRAs) by medullary thymic epithelial cells (mTECs). TRA expression in mTECs mirrors virtually all tissues of the body, irrespective of developmental or spatio-temporal expression patterns. This review summarizes current knowledge on the cellular and molecular regulation of TRA expression in mTECs, outlines relevant mechanisms of antigen presentation and modes of tolerance induction, and discusses implications for the pathogenesis of autoimmune diseases and other biological processes such as fertility, pregnancy, puberty, and tumor defense.

Animals↗
PubMed2005

Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling.

Interleukin 2 signaling is believed to be critically involved in several aspects of CD25(+) CD4(+) regulatory T cell biology, such as intrathymic development, peripheral survival and suppressive function. Here we have analyzed the effects of interleukin 2 or CD25 deficiency on agonist-driven thymic development and the peripheral homeostasis of an antigen-specific population of regulatory T cells positive for forkhead family transcription factor Foxp3 and have correlated our observations with polyclonal suppressor populations. We found that the differentiation, acquisition of functional capacity and formation of a sizeable pool of suppressor T cells in the thymus was independent of interleukin 2 signaling, but that interleukin 2 was essential for the survival of mature Foxp3(+) regulatory T cells.

Animals↗
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↗
PubMed2004

Expression of the B7.1 costimulatory molecule on pancreatic beta cells abrogates the requirement for CD4 T cells in the development of type 1 diabetes.

Although HLA-DQ8 has been implicated as a key determinant of genetic susceptibility to human type 1 diabetes, spontaneous diabetes has been observed in HLA-DQ8 transgenic mice that lack expression of murine MHC class II molecules (mII(-/-)) only when the potent costimulatory molecule, B7.1, is transgenically expressed on pancreatic beta cells. To study the contribution of HLA-DQ8 to the development of diabetes in this model, we crossed RIP-B7.1mII(-/-) mice with a set of transgenic mouse lines that differed in their HLA-DQ8 expression patterns on APC subpopulations, in particular dendritic cells and cortical thymic epithelial cells. Surprisingly, we found that even in the absence of HLA-DQ8 and CD4 T cells, a substantial fraction of the RIP-B7.1mII(-/-) mice developed diabetes. This disease process was remarkable for not only showing insulitis, but also inflammatory destruction of the exocrine pancreas with diffusely up-regulated expression of MHC class I and ICAM-1 molecules. Expression of HLA-DQ8 markedly increased the kinetics and frequency of diabetes, with the most severe disease in the lines with the highest levels of HLA-DQ8 on cortical thymic epithelial cells and the largest numbers of CD4 T cells. However, the adoptive transfer of diabetes was not HLA-DQ8-dependent and disease could be rapidly induced with purified CD8 T cells alone. Expression of B7.1 in the target tissue can thus dramatically alter the cellular and molecular requirements for the development of autoimmunity.

Animals↗
PubMed2003

In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro.

Adoptive transfer of antigen-specific CD25+CD4+ regulatory T cells was used to analyze the stability of their phenotype, their behavior after immunization, and their mode of suppressing cotransferred naive T cells in vivo. We found that regulatory T cells maintained their phenotype in the absence of antigen, were not anergic in vivo, and proliferated as extensively as naive CD4+ T cells after immunization without losing their suppressive function in vivo and in vitro. In vivo, the expansion of cotransferred naive T cells was suppressed relatively late in the response such that regulatory T cells expressing mostly IL-10 but not IL-2 or IFN-gamma represented the dominant subset of cells. Our results reveal properties of regulatory T cells that were not predicted from in vitro studies.

Adoptive Transfer↗
PubMed2003

Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase.

Experiments in nonobese diabetic (NOD) mice that lacked expression of glutamic acid decarboxylase (GAD) in beta cells have suggested that GAD represents an autoantigen essential for initiating and maintaining the diabetogenic immune response. Several attempts of inducing GAD-specific recessive tolerance to support this hypothesis have failed. Here we report on successful tolerance induction by expressing a modified form of GAD under control of the invariant chain promoter resulting in efficient epitope display. In spite of specific tolerance insulitis and diabetes occurred with normal kinetics indicating that GAD is not an essential autoantigen in the pathogenesis of diabetes.

Amino Acid Sequence↗
PubMed2003

Visualizing the course of antigen-specific CD8 and CD4 T cell responses to a growing tumor.

Spontaneous tumors frequently express antigens that can be recognized by the immune system but nevertheless manage to evade immune surveillance. To better understand the mechanism of evasion, we followed CD8 and CD4 T cells reacting against a subcutaneously growing tumor, modified to express influenza hemagglutinin (HA) as surrogate tumor antigen. Adoptive transfer of 8,000 antigen-specific CD8 T cells was sufficient to protect against challenge with 1x10(6) tumor cells, while larger numbers of T cells rejected established tumors. HA-specific CD4 T cells could not reject tumors on their own but helped rejection by CD8 T cells. Rejection of the tumor coincided with prolonged survival of expanded antigen-specific CD8 and CD4 T cells, while a failing anti-tumor response was accompanied by transient expansion followed by rapid elimination of antigen-specific T cells. Thus, a highly immunogenic tumor can evade immune surveillance because of an insufficient number of tumor-specific T cells and antigen overload, resulting in exhaustion of the immune response. In this scenario, adoptive immunotherapy rather than vaccination promises successful treatment.

Animals↗
PubMed2003

Thymic selection revisited: how essential is it?

Intrathymic T cell development represents one of the best studied paradigms of mammalian development. Lymphoid committed precursors enter the thymus and the Notch1 receptor plays an essential role in committing them to the T cell lineages. The pre-T cell receptor (TCR), as an autonomous cell signaling receptor, commits cells to the alphabeta lineage while its rival, the gammadeltaTCR, is involved in generating the gammadelta lineage of T cells. Positive and negative selection of immature alphabetaTCR-expressing cells are essential mechanisms for generating mature T cells, committing them to the CD4 and CD8 lineages and avoiding autoimmunity. Additional lineages of alphabetaT cells, such as the natural killer T cell lineage and the CD25+ regulatory T cell lineage, are formed when the alphabetaTCR encounters specific ligands in suitable microenvironments. Thus, positive selection and receptor-instructed lineage commitment represent a hallmark of the thymus. Ectopically expressed organ-specific antigens contribute to thymic self-nonself discrimination, which represents an essential feature for the evolutionary fitness of mammalian species.

Animals↗
PubMed2002

Projection of an immunological self shadow within the thymus by the aire protein.

Humans expressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorgan autoimmune disease. We used aire- deficient mice to test the hypothesis that this transcription factor regulates autoimmunity by promoting the ectopic expression of peripheral tissue- restricted antigens in medullary epithelial cells of the thymus. This hypothesis proved correct. The mutant animals exhibited a defined profile of autoimmune diseases that depended on the absence of aire in stromal cells of the thymus. Aire-deficient thymic medullary epithelial cells showed a specific reduction in ectopic transcription of genes encoding peripheral antigens. These findings highlight the importance of thymically imposed "central" tolerance in controlling autoimmunity.

Aging↗
PubMed2002

Origin of regulatory T cells with known specificity for antigen.

T cell receptor agonists can induce the differentiation of regulatory T (T(R)) cells. We report here that the immunoglobulin kappa-controlled expression of an agonist in different cell types correlated with the phenotype of the generated T(R) cells. We found that aberrant expression on thymic stroma yielded predominantly CD4(+)CD25(+) T(R) cells, which--under physiological conditions--may be induced by ectopically expressed organ-specific antigens and thus prevent organ-specific autoimmunity. Expression of the agonist antigen by nonactivated hematopoietic cells produced mostly CD4(+)CD25(-) T(R) cells. This subset can be derived from mature monospecific T cells without "tutoring" by other T cells and can be generated in the absence of a functioning thymus. Suppression of CD4(+) T cell proliferative responses by both CD25(+) and CD25(-) subsets was interleukin 10 (IL-10) independent and was overcome by IL-2. These data suggest that distinct pathways can be exploited to interfere with unwanted immune responses.

Animals↗
PubMed2002

Stabilization of beta-catenin induces lesions reminiscent of prostatic intraepithelial neoplasia, but terminal squamous transdifferentiation of other secretory epithelia.

The present study documents that stabilization of beta-catenin is sufficient to induce lesions reminiscent of prostate intraepithelial neoplasia (PIN). Such lesions were present in all compound mutant mice and all prostate acini expressing stabilized beta-catenin. High grade PIN-like lesions resembling early human prostate cancer were detected as early as 10 weeks of age. Surprisingly, stabilization of beta-catenin in other secretory epithelia including salivary, preputial, harderian, and mammary glands induced extensive squamous metaplasia and keratinization associated with terminal differentiation of the target cells, but failed to cause neoplastic transformation. Epidermal hyperplasia, hair follicle cysts, and odontomas were also observed. The prostatic lesions exhibited upregulation of c-myc, increased rate of cellular proliferation, loss of the Na-K-Cl co-transporter NKCC1, and expression of androgen receptor. Basal cell markers such as p63 and keratin 5 were not expressed by the masses of PIN-like lesions, but were present in small foci of proliferating beta-catenin expressing basal cells. Our observations indicate that beta-catenin stabilization is a crucial event for the initiation of PIN-like lesions, but induces squamous metaplasia rather than tumorigenesis in secretory epithelia other than the prostate.

Animals↗
PubMed2002

Cutting edge: Attenuated experimental autoimmune encephalomyelitis in eta-1/osteopontin-deficient mice.

Recent studies indicate that early T lymphocyte activation 1 (Eta-1), also known as osteopontin, is a cytokine contributing to the development of Th1 immunity. In the present report, the role of Eta-1 in experimental autoimmune encephalomyelitis (EAE), a disease associated with Th1 immunity, was examined by analysis of disease progression in Eta-1-deficient (Eta-1-/-) mice. Although incidence and onset of peptide-induced EAE were found to be similar in Eta-1-/- and Eta-1+/+ mice, Eta-1-/- mice displayed significantly lower mean maximal clinical score and faster recovery without spontaneous relapses. Accordingly, decreased inflammatory infiltration and demyelination were observed in the spinal cords of Eta-1-/- mice. Furthermore, in comparison to Eta-1+/+, Eta-1-/- CD4+ T cells had reduced expression of IFN-gamma and TNF-alpha upon ex vivo restimulation. Taken together, these results suggest that Eta-1 may sustain autoimmune responses by assisting in maintenance of Th1 immunity during EAE.

Animals↗