The rockefeller university

Regulatory T cells (Tregs) play crucial roles in both fetal and tumor development. We recently showed that immunosurveillance by pre-existing CD44(high)CD62L(low) activated/memory Tregs (amTregs) specific for self-Ags protects emergent tumor cells in mice. This Treg response of a memory type is more rapid than and dominates the antitumor response of tumor-specific effector T cells. In this study, we report striking similarities between the early Treg responses to embryo and tumor implantation. Tregs are rapidly recruited to uterus-draining lymph nodes and activated in the first days after embryo implantation in both syngeneic and allogeneic matings; express the markers of the amTreg subset; and are at least in part self-Ag specific, as seen in tumor emergence. Unlike in the tumor emergence setting, however, for which preimmunization against tumor Ags is sufficient for complete tumor eradication even in the presence of Tregs, Treg depletion is additionally required for high frequencies of fetus loss after preimmunization against paternal tissue Ags. Thus, amTregs play a major role in protecting embryos in both naive and preimmune settings. This role and the ensuing therapeutic potential are further highlighted by showing that Treg stimulation, directly by low-dose IL-2 or indirectly by Fms-related tyrosine kinase 3 ligand, led to normal pregnancy rates in a spontaneous abortion-prone model.

Ecotypic variation among populations may become associated with widespread genomic differentiation, but theory predicts that this should happen only under particular conditions of gene flow, selection and population size. In closely related species, we might expect the strength of host-associated genomic differentiation (HAD) to be correlated with the degree of phenotypic differentiation in host-adaptive traits. Using microsatellite and Amplified Fragment Length Polymorphism (AFLP) markers, and controlling for isolation by distance between populations, we sought HAD in two congeneric species of butterflies with different degrees of host plant specialization. Prior work on Euphydryas editha had shown strong interpopulation differentiation in host-adapted traits, resulting in incipient reproductive isolation among host-associated ecotypes. We show here that Euphydryas aurinia had much weaker host-associated phenotypic differentiation. Contrary to our expectations, we detected HAD in Euphydryas aurinia, but not in E.editha. Even within an E.aurinia population that fed on both hosts, we found weak but significant sympatric HAD that persisted in samples taken 9years apart. The finding of significantly stronger HAD in the system with less phenotypic differentiation may seem paradoxical. Our findings can be explained by multiple factors, ranging from differences in dispersal or effective population size, to spatial variation in genomic or phenotypic traits and to structure induced by past histories of host-adapted populations. Other infrequently measured factors, such as differences in recombination rates, may also play a role. Our result adds to recent work as a further caution against assumptions of simple relationships between genomic and adaptive phenotypic differentiation.

Measurements are presented of the production of primary K-S(0) and Lambda particles in proton-proton collisions at root s = 7 TeV in the region transverse to the leading charged-particle jet in each event. The average multiplicity and average scalar transverse momentum sum of K-S(0) and Lambda particles measured at pseudorapidities vertical bar eta vertical bar < 2 rise with increasing charged-particle jet p(T) in the range 1-10 GeV/c and saturate in the region 10-50 GeV/c. The rise and saturation of the strange-particle yields and transverse momentum sums in the underlying event are similar to those observed for inclusive charged particles, which confirms the impact-parameter picture of multiple parton interactions. The results are compared to recent tunes of the PYTHIA Monte Carlo event generator. The PYTHIA simulations underestimate the data by 15%-30% for K-S(0) mesons and by about 50% for Lambda baryons, a deficit similar to that observed for the inclusive strange-particle production in non-single-diffractive proton-proton collisions. The constant strange-to charged-particle activity ratios with respect to the leading jet p(T) and similar trends for mesons and baryons indicate that the multiparton-interaction dynamics is decoupled from parton hadronization, which occurs at a later stage.

We present a combination of searches for the standard model Higgs boson using the full CDF run II data set, which corresponds to an integrated luminosity of 9.45-10.0 fb(-1) collected from root s = 1.96 TeV p (p) over bar collisions at the Fermilab Tevatron. The searches consider Higgs boson production from gluon-gluon fusion, vector-boson fusion, and associated production with either a W or Z boson or a t (t) over bar pair. Depending on the production mode, Higgs boson decays to W+W-, ZZ, b (b) over bar, tau(+)tau(-), and gamma gamma are examined. We search for a Higgs boson with masses (m(H)) in the range 90-200 GeV/c(2). In the absence of a signal, we expect based on combined search sensitivity to exclude at the 95% credibility level the mass regions 90 < m(H) < 94 GeV/c(2), 96 < m(H) < 106 GeV/c(2), and 153 < m(H) < 175 GeV/c(2). The observed exclusion regions are 90 < m(H) < 102 GeV/c(2) and 149 < m(H) < 172 GeV/c(2). A moderate excess of signal-like events relative to the background expectation at the level of 2.0 standard deviations is present in the data for the m(H) = 125 GeV/c(2) search hypothesis. We also present interpretations of the data within the context of a fermiophobic model and an alternative standard model incorporating a fourth generation of fermions. Finally, for the hypothesis of a new particle with mass 125 GeV/c(2), we constrain the coupling strengths of the new particle to W-+/- bosons, Z bosons, and fermions.

Background: In Gaucher disease (GD), resulting from mutations in the GBA gene, mutant beta-glucocerebrosidase (GCase) molecules are recognized as misfolded in the endoplasmic reticulum (ER). They are retrotranslocated to the cytoplasm, where they are ubiquitinated and undergo proteasomal degradation in a process known as the ER Associated Degradation (ERAD). We have shown in the past that the degree of ERAD of mutant GCase correlates with GD severity. Persistent presence of mutant, misfolded protein molecules in the ER leads to ER stress and evokes the unfolded protein response (UPR). Methods: We investigated the presence of UPR in several GD models, using molecular and behavioral assays. Results: Our results show the existence of UPR in skin fibroblasts from GD patients and carriers of GD mutations. We could recapitulate UPR in two different Drosophila models for carriers of GD mutations: flies heterozygous for the endogenous mutant GBA orthologs and flies expressing the human N370S or L444P mutant GCase variants. We encountered early death in both fly models, indicating the deleterious effect of mutant GCase during development. The double heterozygous flies, and the transgenic flies, expressing mutant GCase in dopaminergic/serotonergic cells developed locomotion deficit. Conclusion: Our results strongly suggest that mutant GCase induces the UPR in GD patients as well as in carriers of GD mutations and leads to development of locomotion deficit in flies heterozygous for GD mutations.

Small RNAs undergo maturation events that precisely determine the length and structure required for their function. CRISPRs (clustered regularly interspaced short palindromic repeats) encode small RNAs (crRNAs) that together with CRISPR-associated (cas) genes constitute a sequence-specific prokaryotic immune system for anti-viral and anti-plasmid defense. crRNAs are subject to multiple processing events during their biogenesis, and little is known about the mechanism of the final maturation step. We show that in the Staphylococcus epidermidis type III CRISPR-Cas system, mature crRNAs are measured in a Cas10.Csm ribonucleoprotein complex to yield discrete lengths that differ by 6-nucleotide increments. We looked for mutants that impact this crRNA size pattern and found that an alanine substitution of a conserved aspartate residue of Csm3 eliminates the 6-nucleotide increments in the length of crRNAs. In vitro, recombinant Csm3 binds RNA molecules at multiple sites, producing gel-shift patterns that suggest that each protein binds 6 nucleotides of substrate. In vivo, changes in the levels of Csm3 modulate the crRNA size distribution without disrupting the 6-nucleotide periodicity. Our data support a model in which multiple Csm3 molecules within the Cas10.Csm complex bind the crRNA with a 6-nucleotide periodicity to function as a ruler that measures the extent of crRNA maturation.

Merkel cell polyomavirus (MCPyV) is thought to be the etiological agent of Merkel cell carcinoma, but little is known about its distribution and modes of transmission. We conducted seroepidemiological surveys in more than 1000 individuals, from two populations from Cameroon. Overall MCPyV seroprevalence was high in both populations (>75% in adults). Data from the first population, comprising mainly children, indicated that MCPyV infections mostly occurred during early childhood, after the disappearance of specific maternal antibodies. Results from the second family-based population provided evidence for familial aggregation of MCPyV infection status. We observed significant sib-sib correlation (odds ratio = 3.42 [95% CI 1.27-9.19], p = 0.014), particularly for siblings close together in age, and a trend for mother-child correlation (OR = 2.71 [0.86-8.44], p = 0.08). Overall, our results suggest that MCPyV infection is acquired through close contact, possibly involving saliva and/or the skin, especially between young siblings and between mothers and their children. (c) 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Defense against attaching-and-effacing bacteria requires the sequential generation of interleukin 23 (IL-23) and IL-22 to induce protective mucosal responses. Although CD4(+) and NKp46(+) innate lymphoid cells (ILCs) are the critical source of IL-22 during infection, the precise source of IL-23 is unclear. We used genetic techniques to deplete mice of specific subsets of classical dendritic cells (cDCs) and analyzed immunity to the attaching-and-effacing pathogen Citrobacter rodentium. We found that the signaling receptor Notch2 controlled the terminal stage of cDC differentiation. Notch2-dependent intestinal CD11b(+) cDCs were an obligate source of IL-23 required for survival after infection with C. rodentium, but CD103(+) cDCs dependent on the transcription factor Batf3 were not. Our results demonstrate a nonredundant function for CD11b(+) cDCs in the response to pathogens in vivo.

Background Chronic mucocutaneous candidiasis disease (CMCD) may result from various inborn errors of interleukin (IL)-17-mediated immunity. Twelve of the 13 causal mutations described to date affect the coiled-coil domain (CCD) of STAT1. Several mutations, including R274W in particular, are recurrent, but the underlying mechanism is unclear. Objective To investigate and describe nine patients with CMCD in Eastern and Central Europe, to assess the biochemical impact of STAT1 mutations, to determine cytokines in supernatants of Candida-exposed blood cells, to determine IL-17-producing T cell subsets and to determine STAT1 haplotypes in a family with the c.820C>T (R274W) mutation. Results The novel c.537C>A (N179K) STAT1 mutation was gain-of-function (GOF) for -activated factor (GAF)-dependent cellular responses. In a Russian patient, the cause of CMCD was the newly identified c.854 A>G (Q285R) STAT1 mutation, which was also GOF for GAF-dependent responses. The c.1154C>T (T385M) mutation affecting the DNA-binding domain (DBD) resulted in a gain of STAT1 phosphorylation in a Ukrainian patient. Impaired Candida-induced IL-17A and IL-22 secretion by leucocytes and lower levels of intracellular IL-17 and IL-22 production by T cells were found in several patients. Haplotype studies indicated that the c.820C>T (R274W) mutation was recurrent due to a hotspot rather than a founder effect. Severe clinical phenotypes, including intracranial aneurysm, are presented. Conclusions The c.537C>A and c.854A>G mutations affecting the CCD and the c.1154C>T mutation affecting the DBD of STAT1 are GOF. The c.820C>T mutation of STAT1 in patients with CMCD is recurrent due to a hotspot. Patients carrying GOF mutations of STAT1 may develop multiple intracranial aneurysms by hitherto unknown mechanisms.