The rockefeller university

Infectious diseases continue to claim many lives. Prevention of morbidity and mortality from these diseases would benefit not just from new medicines and vaccines but also from a better understanding of what constitutes protective immunity. Among the major immune signals that mobilize host defense against infection is interferon-gamma (IFN-gamma), a protein secreted by lymphocytes. Forty years ago, IFN-gamma was identified as a macrophage-activating factor, and, in recent years, there has been a resurgent interest in IFN-gamma biology and its role in human defense. Here we assess the current understanding of IFN-gamma, revisit its designation as an "interferon," and weigh its prospects as a therapeutic against globally pervasive microbial pathogens.

Sex-limited polymorphism has evolved in many species including our own. Yet, we lack a detailed understanding of the underlying genetic variation and evolutionary processes at work. The brood parasitic common cuckoo (Cuculus canorus) is a prime example of female-limited color polymorphism, where adult males are monochromatic gray and females exhibit either gray or rufous plumage. This polymorphism has been hypothesized to be governed by negative frequency-dependent selection whereby the rarer female morph is protected against harassment by males or from mobbing by parasitized host species. Here, we show that female plumage dichromatism maps to the female-restricted genome. We further demonstrate that, consistent with balancing selection, ancestry of the rufous phenotype is shared with the likewise female dichromatic sister species, the oriental cuckoo (Cuculus optatus). This study shows that sex-specific polymorphism in trait variation can be resolved by genetic variation residing on a sex-limited chromosome and be maintained across species boundaries.

Epstein-Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA-IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA-IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells. IL-27RA-IL-27 has a critical role in the immunity to EBV, and this defence is hijacked by Epstein-Barr virus to promote the expansion of infected transformed B cells

Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1. A systematic review of electronic health records from the BioME Biobank revealed increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals. Finally, treatment of one affected patient with severe atopic dermatitis using the JAK1/JAK2-selective inhibitor, baricitinib, resulted in clinically significant improvement. These findings suggest that individually rare JAK1 GoF variants may underlie an emerging syndrome with more common presentations of autoimmune and inflammatory disease (JAACD syndrome). More broadly, individuals who present with such conditions may benefit from genetic testing for the presence of JAK1 GoF variants.

A search is presented for charged, long-lived supersymmetric particles in final states with one or more disappearing tracks. The search is based on data from proton-proton collisions at a center-of-mass energy of 13 TeV collected with the CMS detector at the CERN LHC between 2016 and 2018, corresponding to an integrated luminosity of 137 fb(-1). The search is performed over final states characterized by varying numbers of jets, b-tagged jets, electrons, and muons. The length of signal-candidate tracks in the plane perpendicular to the beam axis is used to characterize the lifetimes of wino- and Higgsino-like charginos produced in the context of the minimal supersymmetric standard model. The dE/dx energy loss of signal-candidate tracks is used to increase the sensitivity to charginos with a large mass and thus a small Lorentz boost. The observed results are found to be statistically consistent with the background-only hypothesis. Limits on the pair-production cross section of gluinos and squarks are presented in the framework of simplified models of supersymmetric particle production and decay, and for electroweakino production based on models of wino and Higgsino dark matter. The limits presented are the most stringent to date for scenarios with light third-generation squarks and a wino- or Higgsino-like dark matter candidate capable of explaining the observed dark matter relic density.

Lineage plasticity-a state of dual fate expression-is required to release stem cells from their niche constraints and redirect them to tissue compartments where they are most needed. In this work, we found that without resolving lineage plasticity, skin stem cells cannot effectively generate each lineage in vitro nor regrow hair and repair wounded epidermis in vivo. A small-molecule screen unearthed retinoic acid as a critical regulator. Combining high-throughput approaches, cell culture, and in vivo mouse genetics, we dissected its roles in tissue regeneration. We found that retinoic acid is made locally in hair follicle stem cell niches, where its levels determine identity and usage. Our findings have therapeutic implications for hair growth as well as chronic wounds and cancers, where lineage plasticity is unresolved.

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-alpha T cell receptor (pre-TCR alpha) expression. Low circulating naive alpha beta T cell counts at birth persisted over time, with normal memory alpha beta and high gamma delta T cell counts. Their TCR alpha repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue alpha beta T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive alpha beta T cell counts but high gamma delta T cell counts. Although residual pre-TCR alpha expression drove the differentiation of more alpha beta T cells, autoimmune conditions were more frequent in these patients compared with the general population.

The properties of the cell types that are selectively vulnerable in Huntington's disease (HD) cortex, the nature of somatic CAG expansions of mHTT in these cells, and their importance in CNS circuitry have not been delineated. Here, we employed serial fluorescence-activated nuclear sorting (sFANS), deep molecular profiling, and single-nucleus RNA sequencing (snRNA-seq) of motor-cortex samples from thirteen predominantly early stage, clinically diagnosed HD donors and selected samples from cingulate, visual, insular, and prefrontal cortices to demonstrate loss of layer 5a pyramidal neurons in HD. Extensive mHTT CAG expansions occur in vulnerable layer 5a pyramidal cells, and in Betz cells, layers 6a and 6b neurons that are resilient in HD. Retrograde tracing experiments in macaque brains identify layer 5a neurons as corticostriatal pyramidal cells. We propose that enhanced somatic mHTT CAG expansion and altered synaptic function act together to cause corticostriatal disconnection and selective neuronal vulnerability in HD cerebral cortex.

A search for dark matter particles is performed using events with a pair of W bosons and large missing transverse momentum. Candidate events are selected by requiring one or two leptons (l = electrons or muons). The analysis is based on proton-proton collision data collected at a center-of-mass energy of 13TeV by the CMS experiment at the LHC and corresponding to an integrated luminosity of 138 fb(-1). No significant excess over the expected standard model background is observed in the l nu qq and 2l2 nu final states of the W+W- boson pair. Limits are set on dark matter production in the context of a simplified dark Higgs model, with a dark Higgs boson mass above the W+W- mass threshold. The dark matter phase space is probed in the mass range 100-300 GeV, extending the scope of previous searches. Current exclusion limits are improved in the range of dark Higgs masses from 160 to 250 GeV, for a dark matter mass of 200 GeV.

During DNA replication, the proliferating cell nuclear antigen (PCNA) clamps are loaded onto primed sites for each Okazaki fragment synthesis by the AAA+ heteropentamer replication factor C (RFC). PCNA encircling duplex DNA is quite stable and is removed from DNA by the dedicated clamp unloader Elg1-RFC. Here, we show the cryo-EM structure of Elg1-RFC in various states with PCNA. The structures reveal essential features of Elg1-RFC that explain how it is dedicated to PCNA unloading. Specifically, Elg1 contains two external loops that block opening of the Elg1-RFC complex for DNA binding, and an "Elg1 plug" domain that fills the central DNA binding chamber, thereby reinforcing the exclusive PCNA unloading activity of Elg1-RFC. Elg1-RFC was capable of unloading PCNA using non-hydrolyzable AMP-PNP. Both RFC and Elg1-RFC could remove PCNA from covalently closed circular DNA, indicating that PCNA unloading occurs by a mechanism that is distinct from PCNA loading. Implications for the PCNA unloading mechanism are discussed.