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The thioredoxin-1 (Trx1) system is an important contributor to cellular redox balance and is a sensor of energy and glucose metabolism. Here we show critical c-Myc-dependent activation of the Trx1 system during thymocyte and peripheral T-cell proliferation, but repression during T-cell quiescence. Deletion of thioredoxin reductase-1 ( Txnrd1 ) prevents expansion the CD4 − CD8 − thymocyte population, whereas Txnrd1 deletion in CD4 + CD8 + thymocytes does not affect further maturation and peripheral homeostasis of αβT cells. However, Txnrd1 is critical for expansion of the activated T-cell population during viral and parasite infection. Metabolomics show that TrxR1 is essential for the last step of nucleotide biosynthesis by donating reducing equivalents to ribonucleotide reductase. Impaired availability of 2′-deoxyribonucleotides induces the DNA damage response and cell cycle arrest of Txnrd1 -deficient T cells. These results uncover a pivotal function of the Trx1 system in metabolic reprogramming of thymic and peripheral T cells and provide a rationale for targeting Txnrd1 in T-cell leukemia. Thioredoxin (Trx), Trx reductase, Txnip and NADPH together comprise the Trx system. Here the authors make a T cell-specific thioredoxin reductase-1 knockout mouse to show how this system reprograms cellular metabolism to enable T cell development, proliferation and responses.

Nuclear factor-κB (NF-κB) is a transcription factor with a key role in a great variety of cellular processes from embryonic development to immunity, the outcome of which depends on the fine-tuning of NF-κB activity. The development of sensitive and faithful reporter systems to accurately monitor the activation status of this transcription factor is therefore desirable. To address this need, over the years a number of different approaches have been used to generate NF-κB reporter mice, which can be broadly subdivided into bioluminescence- and fluorescence-based systems. While the former enables whole-body visualization of the activation status of NF-κB, the latter have the potential to allow the analysis of NF-κB activity at single-cell level. However, fluorescence-based reporters frequently show poor sensitivity and excessive background or are incompatible with high-throughput flow cytometric analysis. In this work we describe the generation and analysis of ROSA26 knock-in NF-κB reporter (KappaBle) mice containing a destabilized EGFP, which showed sensitive, dynamic, and faithful monitoring of NF-κB transcriptional activity at the single-cell level of various cell types during inflammatory and infectious diseases.

Effective anti-tumor immunity is driven by cytotoxic CD8 + T cells with specificity for tumor antigens. However, the factors that control successful tumor rejection are not well understood. Here we identify a subpopulation of CD8 + T cells that are tumor-antigen-specific and can be identified by KIR expression but paradoxically impair anti-tumor immunity in patients with melanoma. These tumor-antigen-specific KIR + CD8 + regulatory T cells target other tumor-antigen-specific CD8 + T cells, can be detected in both the tumor and the blood, have a conserved transcriptional program and are associated with a poor overall survival. These findings broaden our understanding of the transcriptional and functional heterogeneity of human CD8 + T cells and implicate KIR + CD8 + regulatory T cells as a cellular mediator of immune evasion in human cancer. Tumor-antigen-specific CD8 + T cells are generally thought to help fight against cancer, but here the authors identify a subpopulation of CD8 + T cells that are associated with a poor clinical outcome in melanoma. Although these cells can recognize tumor antigens, they suppress cancer immunity.

BackgroundIdentification and characterization of the antigen specificity of tumor-infiltrating lymphocytes (TILs) are key to understand anti-tumor immunity and can guide the development of novel and effective immunotherapies. Our DECODE® platform enables the identification of TCR and peptide-MHC (pMHC) across the immune synapse of TILs.MethodsTo investigate the T cell response directed against the melanoma antigen landscape, we performed a comprehensive analysis of tumor-infiltrating lymphocytes (TILs) derived from 21 melanoma patients. We employed two complementary approaches that support our DECODE ® platform: (1) an engineered reporter cell system expressing chimeric pMHC-TCR (MCR) hybrid molecules, loaded with tens of thousands of peptides derived from antigens highly expressed in melanoma; and (2) a high-throughput TIL screening platform using barcoded peptide-HLA tetramers. These approaches incorporated diverse libraries that allowed us to broadly screen hundreds of antigens across 68 HLA alleles, enabling the in-depth discovery, validation, and application of TCR-epitope pairs. Immunogenicity of the identified epitopes was tested by assessing their ability to activate T cells in vitro.ResultsBy using our TCR-pMHC DECODE® technologies, we identified a broad repertoire of pMHC-TCR pairs from TILs derived from melanoma patients. The epitopes originated from tumor-associated antigens (TAAs), tumor-specific antigens (TSAs), personalized neoantigens, and Dark Antigens, a group of cancer targets derived from otherwise non-coding genetic regions. In-depth analysis of one patient revealed tumor-specific dark antigens recognized by TIL-derived TCRs, which were also detectable in peripheral blood, suggesting systemic immunologic prevalence.Epitopes from these antigens were tested for immunogenicity using in vitro expansion approaches; we observed Dark Antigen epitope-specific T cell expansion, supporting a role for integration of these epitopes into cancer vaccine approaches. Likewise, decoded TCRs were expressed in primary T cells, and the recombinant TCR-T cells were activated by cell lines derived from multiple solid tumor types, highlighting the therapeutic potential of these TCRs for both cell therapy and bispecific engager formats.ConclusionsThese findings showcase the power of our DECODE® technology to uncover clinically relevant, TIL-derived epitopes and TCRs from TAAs, TSAs, personalized neoantigens and, dark antigens for next-generation cancer immunotherapies that include TCR bispecifics and cancer vaccines. Application of this approach will provide more effective immunotherapies for many solid tumor indications.

In 1993, New Zealand's voters raised a political shockwave: In a binding referendum, a majority decided to replace the first-past-the-post electoral system (FPTP) and to introduce a mixed-member-proportional system (MMP), as used in Germany, instead. Bearing in mind the traditionally stable character of electoral systems, the question arises whether the New Zealand electoral reform can be best explained as accident, product of constitutional design or the result of a long-term evolutionary process. Of these three, the evolutionary model offers a wide range of plausible reasons for this reform. It best explains this exceptional process of institutional learning and maintains plausibility in other cases as well. Nevertheless, the New Zealand example also makes clear that electoral reforms often prove to be a combination of the elements of accident, design and evolution. Reprinted by permission of the VS Verlag für Sozialwissenschaften, Germany

In 1993, New Zealand's voters raised a political shockwave: In a binding referendum, a majority decided to replace the first-past-the-post electoral system (FPTP) and to introduce a mixed-member-proportional system (MMP), as used in Germany, instead. Bearing in mind the traditionally stable character of electoral systems, the question arises whether the New Zealand electoral reform can be best explained as accident, product of constitutional design or the result of a long-term evolutionary process. Of these three, the evolutionary model offers a wide range of plausible reasons for this reform. It best explains this exceptional process of institutional learning and maintains plausibility in other cases as well. Nevertheless, the New Zealand example also makes clear that electoral reforms often prove to be a combination of the elements of accident, design and evolution.

The cross section of the \\(t\\bar{t}Z\\)~and \\(t\\bar{t}W\\)~processes are measured in a simultaneous fit using 36.1 \\(\\text{fb}^{-1}\\) of of proton--proton collisions at a centre-of-mass energy of \\(\\sqrt{s}=13\\) TeV recorded by the ATLAS experiment at the LHC. In addition, a fit is performed in the 4\\(\\ell\\) channel only, resulting in a cross section of \\(\\sigma_{t\\bar{t}Z} = 1.07 \\pm 0.26 \\,\\text{pb}\\). This result is consistent with the combined fit and agrees with the prediction by the Standard Model.

The cross section of the \\(t\\bar{t}Z\\) and \\(t\\bar{t}W\\) processes are measured in a simultaneous fit using 36.1 \\(\\text{fb}^{-1}\\) of proton-proton collisions at a centre of mass energy of \\(\\sqrt{s}=13\\) TeV recorded by the ATLAS detector at the LHC. The result is found to be \\(\\sigma_{t\\bar{t}Z} = 0.95 \\pm 0.08 \\text{ (stat.)} \\pm 0.10 \\text{ (syst.)}\\,\\text{pb}\\) and \\(\\sigma_{t\\bar{t}W} = 0.87 \\pm 0.13 \\text{ (stat.)} \\pm 0.14 \\text{ (syst.)}\\,\\text{pb}\\) and compatible with the Standard Model.

Nuclear factor-kB (NF-kB) is a transcription factor with a key role in a great variety of cellular processes from embryonic development to immunity, the outcome of which depends on the fine-tuning of NF-kB activity. The development of sensitive and faithful reporter systems to accurately monitor the activation status of this transcription factor is therefore desirable. To address this need, over the years a number of different approaches have been used to generate NF-kB reporter mice, which can be broadly subdivided into bioluminescence- and fluorescence-based systems. While the former enables whole-body visualization of the activation status of NF-kB, the latter have the potential to allow the analysis of NF-kB activity at single cell level. However, fluorescence-based reporters frequently show poor sensitivity and excessive background or are incompatible with high-throughput flow cytometric analysis. In this work we describe the generation and analysis of ROSA26 knockin NF-kB reporter (KappaBle) mice containing a destabilized EGFP, which showed sensitive, dynamic, and faithful monitoring of NF-kB activity at the single-cell level of various cell types during inflammatory and infectious diseases. Competing Interest Statement The authors have declared no competing interest.