Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Gene-edited pigs: a translational model for human food allergy against alpha-Gal and anaphylaxis

The prevalence of food allergy is rising and is estimated to approach 10%. Red meat allergy is the first known food allergy elicited by immunoglobulin E (IgE) antibodies recognizing a carbohydrate. Due to the loss of function of the alpha−1,3−galactosyltransferase (GGTA1) gene in humans, the disaccharide galactose-α-1,3-galactose (α-Gal) cannot be synthesized and therefore became immunogenic. IgE sensitization is elicited through the skin by repetitive tick bites transmitting α-Gal. The underlying mechanisms regarding innate and adaptive immune cell activation, including the B-cell isotype switch to IgE, are poorly understood, requiring further research and physiologically relevant animal models. Here, we describe a new animal model of red meat allergy using percutaneous α-Gal sensitization of gene-edited GGTA1-deficient pigs. Total and α-Gal-specific IgG, IgG1, IgG2, IgG4, and IgE levels were tracked. Further key factors associated with allergic skin inflammation, type 2 immunity, and allergy development were measured in PBMCs and skin samples. Significant increases in α-Gal-specific IgG1 and IgE levels indicated successful sensitization to the allergen α-Gal. Intracutaneous sensitizations with α-Gal recruited lymphocytes to the skin, including elevated numbers of T helper 2 (Th2) cells. Finally, α-Gal-sensitized pigs not only recognized α-Gal as non-self-antigen following α-Gal exposure through the skin but also developed anaphylaxis upon antigen challenge. Based on the similarities between the porcine and human skin, this new large animal model for α-Gal allergy should help to unveil the consecutive steps of cutaneous sensitization and aid the development of prophylactic and treatment interventions

Regulatory T cells characterized by low Id3 expression are highly suppressive and accumulate during chronic infection

Foxp3(+) regulatory T (Treg) cells are broadly divided into naive-like and activated Treg cells, however recent studies suggest further Treg cell heterogeneity. Treg cells contribute to impaired T cell responses in chronic infections, but the role of specific Treg cell subpopulations in viral infections is not well defined. Here, we report that activated Treg cells are separated into two transcriptionally distinct subpopulations characterized by low or high expression of the transcriptional regulator Id3. Id3(lo) Treg cells are a highly suppressive Treg cell subpopulation, expressing elevated levels of immunomodulatory molecules and are capable of broadly targeting T cell responses. Viral infection and interleukin-2 promote the differentiation of Id3(hi) into Id3(lo) Treg cells and during chronic infection Id3(lo) Treg cells are the predominant Treg cell population. Thus, our report provides a framework, in which different activated Treg cell subpopulations specifically affect immune responses, possibly contributing to T cell dysfunction in chronic infections.Funding Agencies|International Graduate Academy fellowship; Fill-in-the-gap stipend; German Research Foundation [DFG SCHA 1442/5-1, DFG SCHA 1442/6-1, DFG SFB1160-IMPATH TP2]; Federal Ministry of Education and Research [BMBF 01EO1303]; European Commission [FP7 PIRG08-GA-2010-276906]; Muller-Fahnenberg Stiftung; German Research Foundation (DFG) [SFB1160-IMPATH TP5]</p

Id3 Maintains Foxp3 Expression in Regulatory T Cells by Controlling a TranscriptionalNetwork of E47, Spi-B, and SOCS3

The transcription factor Foxp3 dominantly controls regulatory T (Treg) cell function, and only its continuous expression guarantees the maintenance of full Treg cell-suppressive capacity. However, transcriptional regulators maintaining Foxp3 transcription are incompletely described. Here, we report that high E47 transcription factor activity in Treg cells resulted in unstable Foxp3 expression. Under homeostatic conditions, Treg cells expressed high levels of the E47 antagonist Id3, thus restricting E47 activity and maintaining Foxp3 expression. In contrast, stimulation of Id3-deficient or E47-overexpressing Treg cells resulted in the loss of Foxp3 expression in a subset of Treg cells in vivo and in vitro. Mechanistic analysis indicated that E47 activated expression of the transcription factor Spi-B and the suppressor of cytokine signaling 3 (SOCS3), which both downregulated Foxp3 expression. These findings demonstrate that the balance of Id3 and E47 controls the maintenance of Foxp3 expression in Treg cells and, thus, contributes to Treg cell plasticity.Funding Agencies|International Graduate Academy fellowship; Max Planck Institute; German Research Foundation [DFG SCHA 1442/3-2, SCHA 1442/5-1]; Federal Ministry of Education and Research [BMBF 01EO1303]; European Commission [FP7 PIRG08-GA-2010-276906]; Muller-Fahnenberg Stiftung</p

Inflammatory Cues Direct Skin-Resident Type 1 Innate Lymphoid Cells to Adopt a Psoriasis-Promoting Identity

Innate lymphoid cells (ILCs) are gatekeepers in barrier organs, where they maintain tissue integrity and contribute to host defense as well as tissue repair. Inappropriate activation of ILCs, however, can lead to immunopathology with detrimental results. In this study, we focused on type 1 ILCs (ILC1s), which under inflammatory conditions constitute a poorly defined population with ambiguous functions. To delineate the properties of ILC1s in skin pathology, we used the well-established mouse model of imiquimod-induced psoriasis. Although ILC1s represented a minority among cutaneous lymphocytes in vehicle-treated controls, they rapidly expanded during early psoriasis and ultimately increased by >20-fold. This rapid increase was verified using two additional psoriasis models. Inflammatory ILC1s from imiquimod-treated skin were defined as CD44+, CXCR6+, and CD11b+ and substantially contributed to TNF-α and GM-CSF production, rendering them a potential candidate to shape the inflammatory infiltrate. In accordance with the psoriasis-specific microenvironment, skin ILC1s upregulated the IL-23 receptor whereas expression of the IL-12Rβ2 subunit was diminished. As a consequence, neutralization of IL-12 only had a minor impact, whereas blocking IL-23 reduced both ILC1 abundance and disease severity. Together, our findings identify skin ILC1s as a likely player in early psoriasis and a prospective target for therapeutic approaches

The Concerted Action of E2-2 and HEB Is Critical for Early Lymphoid Specification

The apparition of adaptive immunity in Gnathostomata correlates with the expansion of the E-protein family to encompass E2-2, HEB, and E2A. Within the family, E2-2 and HEB are more closely evolutionarily related but their concerted action in hematopoiesis remains to be explored. Here we show that the combined disruption of E2-2 and HEB results in failure to express the early lymphoid program in Common lymphoid precursors (CLPs) and a near complete block in B-cell development. In the thymus, Early T-cell progenitors (ETPs) were reduced and T-cell development perturbed, resulting in reduced CD4 T- and increased γδ T-cell numbers. In contrast, hematopoietic stem cells (HSCs), erythro-myeloid progenitors, and innate immune cells were unaffected showing that E2-2 and HEB are dispensable for the ancestral hematopoietic lineages. Taken together, this E-protein dependence suggests that the appearance of the full Gnathostomata E-protein repertoire was critical to reinforce the gene regulatory circuits that drove the emergence and expansion of the lineages constituting humoral immunity

Fetal Tissue-Derived Mast Cells (MC) as Experimental Surrogate for In Vivo Connective Tissue MC

Bone-marrow-derived mast cells are matured from bone marrow cells in medium containing 20% fetal calf serum (FCS), interleukin (IL)-3 and stem-cell factor (SCF) and are used as in vitro models to study mast cells (MC) and their role in health and disease. In vivo, however, BM-derived hematopoietic stem cells account for only a fraction of MC; the majority of MC in vivo are and remain tissue resident. In this study we established a side-by-side culture with BMMC, fetal skin MC (FSMC) or fetal liver MC (FLMC) for comparative studies to identify the best surrogates for mature connective tissue MC (CTMC). All three MC types showed comparable morphology by histology and MC phenotype by flow cytometry. Heterogeneity was detected in the transcriptome with the most differentially expressed genes in FSMC compared to BMMC being Hdc and Tpsb2. Expression of ST2 was highly expressed in BMMC and FSMC and reduced in FLMC, diminishing their secretion of type 2 cytokines. Higher granule content, stronger response to FcεRI activation and significantly higher release of histamine from FSMC compared to FLMC and BMMC indicated differences in MC development in vitro dependent on the tissue of origin. Thus, tissues of origin imprint MC precursor cells to acquire distinct phenotypes and signatures despite identical culture conditions. Fetal-derived MC resemble mature CTMC, with FSMC being the most developed

Searches for the ZγZ\gamma decay mode of the Higgs boson and for new high-mass resonances in pppp collisions at s=13\sqrt{s} = 13 TeV with the ATLAS detector

International audienceThis article presents searches for the Zγ decay of the Higgs boson and for narrow high-mass resonances decaying to Zγ, exploiting Z boson decays to pairs of electrons or muons. The data analysis uses 36.1 fb$^{−1}$ of pp collisions at $\sqrt{s}=13$ recorded by the ATLAS detector at the CERN Large Hadron Collider. The data are found to be consistent with the expected Standard Model background. The observed (expected — assuming Standard Model pp → H → Zγ production and decay) upper limit on the production cross section times the branching ratio for pp → H → Zγ is 6.6. (5.2) times the Standard Model prediction at the 95% confidence level for a Higgs boson mass of 125.09 GeV. In addition, upper limits are set on the production cross section times the branching ratio as a function of the mass of a narrow resonance between 250 GeV and 2.4 TeV, assuming spin-0 resonances produced via gluon-gluon fusion, and spin-2 resonances produced via gluon-gluon or quark-antiquark initial states. For high-mass spin-0 resonances, the observed (expected) limits vary between 88 fb (61 fb) and 2.8 fb (2.7 fb) for the mass range from 250 GeV to 2.4 TeV at the 95% confidence level

Search for direct top squark pair production in final states with two leptons in s=13\sqrt{s} = 13 TeV pppp collisions with the ATLAS detector

International audienceThe results of a search for direct pair production of top squarks in events with two opposite-charge leptons (electrons or muons) are reported, using $36.1~\hbox {fb}^{-1}$ of integrated luminosity from proton–proton collisions at $\sqrt{s}=13$ TeV collected by the ATLAS detector at the Large Hadron Collider. To cover a range of mass differences between the top squark $\tilde{t}$ and lighter supersymmetric particles, four possible decay modes of the top squark are targeted with dedicated selections: the decay $\tilde{t} \rightarrow b \tilde{\chi }_{1}^{\pm }$ into a b-quark and the lightest chargino with $\tilde{\chi }_{1}^{\pm } \rightarrow W \tilde{\chi }_{1}^{0}$ , the decay $\tilde{t} \rightarrow t \tilde{\chi }_{1}^{0}$ into an on-shell top quark and the lightest neutralino, the three-body decay $\tilde{t} \rightarrow b W \tilde{\chi }_{1}^{0}$ and the four-body decay $\tilde{t} \rightarrow b \ell \nu \tilde{\chi }_{1}^{0}$ . No significant excess of events is observed above the Standard Model background for any selection, and limits on top squarks are set as a function of the $\tilde{t}$ and $\tilde{\chi }_{1}^{0}$ masses. The results exclude at 95% confidence level $\tilde{t}$ masses up to about 720 GeV, extending the exclusion region of supersymmetric parameter space covered by previous searches