Person: von Boehmer, Harald
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von Boehmer
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Harald
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von Boehmer, Harald
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Publication Reply to “Tolerogenic insulin peptide therapy precipitates type 1 diabetes”(The Rockefeller University Press, 2017) Daniel, Carolin; Weigmann, Benno; von Boehmer, HaraldIn this issue of JEM, Bergman et al. (https://doi.org/10.1084/jem.20160471) challenge the data published in our previous JEM paper on the preventive effect of tolerogenic vaccination with a strong agonist insulin mimetope in type 1 diabetes. Here, we provide a response to these data and suggest that appropriate subimmunogenic conditions are required to induce Foxp3+ regulatory T cell conversion.Publication The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia(The Rockefeller University Press, 2013) Mansour, Marc R.; Sanda, Takaomi; Lawton, Lee N.; Li, Xiaoyu; Kreslavsky, Taras; Novina, Carl; Brand, Marjorie; Gutierrez, Alejandro; Kelliher, Michelle A.; Jamieson, Catriona H.M.; von Boehmer, Harald; Young, Richard A.; Look, A.The oncogenic transcription factor TAL1/SCL is aberrantly expressed in 60% of cases of human T cell acute lymphoblastic leukemia (T-ALL) and initiates T-ALL in mouse models. By performing global microRNA (miRNA) expression profiling after depletion of TAL1, together with genome-wide analysis of TAL1 occupancy by chromatin immunoprecipitation coupled to massively parallel DNA sequencing, we identified the miRNA genes directly controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. The most dynamically regulated miRNA was miR-223, which is bound at its promoter and up-regulated by the TAL1 complex. miR-223 expression mirrors TAL1 levels during thymic development, with high expression in early thymocytes and marked down-regulation after the double-negative-2 stage of maturation. We demonstrate that aberrant miR-223 up-regulation by TAL1 is important for optimal growth of TAL1-positive T-ALL cells and that sustained expression of miR-223 partially rescues T-ALL cells after TAL1 knockdown. Overexpression of miR-223 also leads to marked down-regulation of FBXW7 protein expression, whereas knockdown of TAL1 leads to up-regulation of FBXW7 protein levels, with a marked reduction of its substrates MYC, MYB, NOTCH1, and CYCLIN E. We conclude that TAL1-mediated up-regulation of miR-223 promotes the malignant phenotype in T-ALL through repression of the FBXW7 tumor suppressor.Publication Negative selection, not receptor editing, is a physiological response of autoreactive thymocytes(The Rockefeller University Press, 2013) Kreslavsky, Taras; Kim, Hye-Jung; Koralov, Sergei B.; Ghitza, Dvora; Buch, Thorsten; Cantor, Harvey; Rajewsky, Klaus; von Boehmer, HaraldAntigen receptor editing—a process of secondary rearrangements of antigen receptor genes in autoreactive lymphocytes—is a well-established tolerance mechanism in B cells, whereas its role in T cells remains controversial. Here, we investigated this issue using a novel Tcra knock-in locus, which ensured appropriate timing of TCRα expression and allowed secondary rearrangements. Under these conditions the only response to self-antigen that could be unambiguously identified was negative selection of CD4/CD8 double positive thymocytes. No evidence could be obtained for antigen-induced TCR editing, whereas replacement of the transgenic TCRα chain by ongoing gene rearrangement occurred in some cells irrespective of the presence or absence of self-antigen.Publication Deciphering Thymic Development(Frontiers Media S.A., 2014) von Boehmer, HaraldPublication PLZF Controls the Expression of a Limited Number of Genes Essential for NKT Cell Function(Frontiers Media S.A., 2012) Gleimer, Michael; von Boehmer, Harald; Kreslavsky, TarasNatural killer (NKT) T cells exhibit tissue distribution, surface phenotype, and functional responses that are strikingly different from those of conventional T cells. The transcription factor PLZF is responsible for most of these properties, as its ectopic expression in conventional T cells is sufficient to confer to them an NKT-like phenotype. The molecular program downstream of PLZF, however, is largely unexplored. Here we report that PLZF regulates the expression of a surprisingly small set of genes, many with known immune functions. This includes several established components of the NKT cell developmental program. Expression of the transcriptional regulators Id2, previously shown to be required for iNKT cell survival in the liver and c-Maf, which shapes the NKT cytokine profile, was compromised in PLZF-deficient cells. Ectopic expression of c-Maf complemented the cells’ defect in producing IL-4 and IL-10. PLZF also induced a program of cell surface receptors which shape the NKT cell’s response to external stimuli, including the costimulatory receptor ICOS and the cytokine receptors IL12rb1 and IL18r1. As an ensemble, the known functions of the molecules whose expression is affected by PLZF explain many defects observed in \(PLZF^{−/−}\) NKT cells.Publication Prevention of Type 1 Diabetes in Mice by Tolerogenic Vaccination with a Strong Agonist Insulin Mimetope(The Rockefeller University Press, 2011) Daniel, Carolin; Weigmann, Benno; Bronson, Roderick; von Boehmer, HaraldType 1 diabetes (T1D) results from the destruction of insulin-secreting pancreatic cells by autoreactive T cells. Insulin is an essential target of the autoimmune attack. Insulin epitopes recognized by diabetogenic T cell clones bind poorly to the class II I-A\(^{g7}\) molecules of nonobese diabetic (NOD) mice, which results in weak agonistic activity of the peptide MHC complex. Here, we describe a strongly agonistic insulin mimetope that effectively converts naive T cells into Foxp3\(^+\) regulatory T cells in vivo, thereby completely preventing T1D in NOD mice. In contrast, natural insulin epitopes are ineffective. Subimmunogenic vaccination with strongly agonistic insulin mimetopes might represent a novel strategy to prevent T1D in humans at risk for the disease.Publication Smad3 binding to the foxp3 enhancer is dispensable for the development of regulatory T cells with the exception of the gut(The Rockefeller University Press, 2012) Schlenner, Susan M.; Weigmann, Benno; Ruan, Qingguo; Chen, Youhai; von Boehmer, HaraldRegulatory T cells (T reg cells) are essential for the prevention of autoimmunity throughout life. T reg cell development occurs intrathymically but a subset of T reg cells can also differentiate from naive T cells in the periphery. In vitro, Smad signaling facilitates conversion of naive T cells into T reg cells but results in unstable Foxp3 expression. The TGF-β–Smad response element in the foxp3 locus is located in the CNS1 region in close proximity to binding sites for transcription factors implicated in TCR and retinoic acid signaling. From in vitro experiments it was previously postulated that foxp3 transcription represents a hierarchical process of transcription factor binding in which Smad3 would play a central role in transcription initiation. However, in vitro conditions generate T reg cells that differ from T reg cells encountered in vivo. To address the relevance of Smad3 binding to the CNS1 enhancer in vivo, we generated mice that exclusively lack the Smad binding site (foxp3CNS1mut). We show that binding of Smad3 to the foxp3 enhancer is dispensable for T reg cell development in newborn and adult mice with the exception of the gut.Publication Retinoic Acid Can Enhance Conversion of Naive into Regulatory T Cells Independently of Secreted Cytokines(The Rockefeller University Press, 2009) Nolting, Jens; Reuter, Sabine; Stuelten, Christina; Li, Peng; Sucov, Henry; Kim, Byung-Gyu; Letterio, John J.; Kretschmer, Karsten; Daniel, Carolin; Kim, Hye-Jung; von Boehmer, HaraldIt has been reported that retinoic acid (RA) enhances regulatory T (T reg) cell conversion by inhibiting the secretion of cytokines that interfere with conversion. This report shows that these conclusions provide a partial explanation at best. First, RA not only interfered with cytokine secretion but also with the ability of these cytokines to inhibit T reg cell conversion of naive T cells. Furthermore, RA enhanced conversion even in the absence of inhibitory cytokines. The latter effect depended on the RA receptor α (RARα) but did not require Smad3, despite the fact that RA enhanced Smad3 expression. The RARα1 isoform was not essential for RA-dependent enhancement of transforming growth factor β–driven conversion, suggesting that conversion can also be mediated by RARα2. Interleukin (IL)-6 strongly reduced RARα expression levels such that a deficiency of the predominant RARα1 isoform leaves too little RARα2 for RA to inhibit the generation of Th17 cells in the presence of IL-6.Publication Lineage Diversion of T Cell Receptor Transgenic Thymocytes Revealed by Lineage Fate Mapping(Public Library of Science, 2008) Egawa, Takeshi; Kreslavsky, Taras; Littman, Dan R.; Alberola-Ila, Jose; von Boehmer, HaraldBackground: The binding of the T cell receptor (TCR) to major histocompatibility complex (MHC) molecules in the thymus determines fates of \(TCR\alpha\beta\) lymphocytes that subsequently home to secondary lymphoid tissue. TCR transgenic models have been used to study thymic selection and lineage commitment. Most TCR transgenic mice express the rearranged \(TCR\alpha\beta\) prematurely at the double negative stage and abnormal TCRαβ populations of T cells that are not easily detected in non-transgenic mice have been found in secondary lymphoid tissue of TCR transgenic mice. Methodology and Principal Findings: To determine developmental pathways of TCR-transgenic thymocytes, we used Cre-LoxP-mediated fate mapping and show here that premature expression of a transgenic \(TCR\alpha\beta\) diverts some developing thymocytes to a developmental pathway which resembles that of gamma delta cells. We found that most peripheral T cells with the HY-TCR in male mice have bypassed the RORγt-positive \(CD4^{+}8^{+}\) (double positive, DP) stage to accumulate either as \(CD4^{-}8^{-}\) (double negative, DN) or as \(CD8\alpha^{+}\) T cells in lymph nodes or gut epithelium. Likewise, DN \(TCR\alpha\beta\) cells in lymphoid tissue of female mice were not derived from DP thymocytes. Conclusion: The results further support the hypothesis that the premature expression of the \(TCR\alpha\beta\) can divert DN thymocytes into gamma delta lineage cells.Publication Transgenically Induced GAD Tolerance Curtails the Development of Early β-Cell Autoreactivities but Causes the Subsequent Development of Supernormal Autoreactivities to Other β-Cell Antigens(American Diabetes Association, 2009) Tian, Jide; Dang, Hoa; von Boehmer, Harald; Jaeckel, Elmar; Kaufman, Daniel L.Objective: To study how tolerance to GAD65 affects the development of autoimmunity to other β-cell autoantigens (β-CAAs) in GAD65-transgenic (GAD-tg) NOD mice. Research Designs and Methods: We used ELISPOT to characterize the frequency and functional phenotype of T-cell responses to GAD65 and other β-CAAs at different ages in GAD-tg mice and their NOD mouse littermates. Results: In young GAD-tg mice, Th1 responses to GAD65's dominant determinants were 13−18% of those in young NOD mice. This coincided with a great reduction in Th1 responses to other β-CAAs. Evidently, GAD65-reactive T-cells are important for activating and/or expanding early autoreactivities in NOD mice. As GAD-tg mice aged, their T-cell responses to GAD65 remained low, but they developed supernormal splenic and pancreatic lymph node T-cell autoimmunity to other β-CAAs. Apparently, the elimination/impairment of many GAD65-reactive T-cells allowed other β-CAA–reactive T-cells to eventually expand to a greater extent, perhaps by reducing competition for antigen-presenting cells, or homeostatic proliferation in the target tissue, which may explain the GAD-tg mouse's usual disease incidence. Conclusions: Transgenically induced reduction of GAD65 autoreactivity curtailed the development of early T-cell responses to other β-CAAs. However, later in life, β-CAA–reactive T-cells expanded to supernormal levels. These data suggest that early β-cell autoreactivities are mutually dependent for support to activate and expand, while later in the disease process, autoantigen-specific T-cell pools can expand autonomously. These findings have implications for understanding type 1 diabetes immunopathogenesis and for designing antigen-based immunotherapeutics.