Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype

The immune system must distinguish not only between self and non-self, but also between innocuous and pathological foreign antigens to prevent unnecessary or self-destructive immune responses. Unresponsiveness to harmless antigens is established through central and peripheral processes. Whereas clonal deletion and anergy are mechanisms of peripheral tolerance, active suppression by T-regulatory 1 (Tr1) cells has emerged as an essential factor in the control of autoreactive cells. Tr1 cells are CD4+ T lymphocytes that are defined by their production of interleukin 10 (IL-10) and suppression of T-helper cells; however, the physiological conditions underlying Tr1 differentiation are unknown. Here we show that co-engagement of CD3 and the complement regulator CD46 in the presence of IL-2 induces a Tr1-specific cytokine phenotype in human CD4+ T cells. These CD3/CD46-stimulated IL-10-producing CD4+ cells proliferate strongly, suppress activation of bystander T cells and acquire a memory phenotype. Our findings identify an endogenous receptor-mediated event that drives Tr1 differentiation and suggest that the complement system has a previously unappreciated role in T-cell-mediated immunity and tolerance.     

The methylated component of the Neurospora crassa genome

Cytosine methylation is common, but not ubiquitous, in eukaryotes. Mammals and the fungus Neurospora crassa have about 2-3% of cytosines methylated. In mammals, methylation is almost exclusively in the under-represented CpG dinucleotides, and most CpGs are methylated whereas in Neurospora, methylation is not preferentially in CpG dinucleotides and the bulk of the genome is unmethylated. DNA methylation is essential in mammals but is dispensable in Neurospora, making this simple eukaryote a favoured organism in which to study methylation. Recent studies indicate that DNA methylation in Neurospora depends on one DNA methyltransferase, DIM-2 (ref. 6), directed by a histone H3 methyltransferase, DIM-5 (ref. 7), but little is known about its cellular and evolutionary functions. As only four methylated sequences have been reported previously in N. crassa, we used methyl-binding-domain agarose chromatography to isolate the methylated component of the genome. DNA sequence analysis shows that the methylated component of the genome consists almost exclusively of relics of transposons that were subject to repeat-induced point mutation--a genome defence system that mutates duplicated sequences.     

Magnetic enhancement of superconductivity from electron spin domains

Since the discovery of superconductivity, there has been a drive to understand the mechanisms by which it occurs. The BCS (Bardeen-Cooper-Schrieffer) model successfully treats the electrons in conventional superconductors as pairs coupled by phonons (vibrational modes of oscillation) moving through the material, but there is as yet no accepted model for high-transition-temperature, organic or 'heavy fermion' superconductivity. Experiments that reveal unusual properties of those superconductors could therefore point the way to a deeper understanding of the underlying physics. In particular, the response of a material to a magnetic field can be revealing, because this usually reduces or quenches superconductivity. Here we report measurements of the heat capacity and magnetization that show that, for particular orientations of an external magnetic field, superconductivity in the heavy-fermion material CeCoIn(5) is enhanced through the magnetic moments (spins) of individual electrons. This enhancement occurs by fundamentally altering how the superconducting state forms, resulting in regions of superconductivity alternating with walls of spin-polarized unpaired electrons; this configuration lowers the free energy and allows superconductivity to remain stable. The large magnetic susceptibility of this material leads to an unusually strong coupling of the field to the electron spins, which dominates over the coupling to the electron orbits.     

Mothers with living children and children with living mothers: the role of fertility and mortality in the period 1911-2050

Whether an individual has one or more surviving children at a given age and/or a surviving parent depends both on fertility (not only number of children, but also timing of childbearing) and mortality. We consider the contribution of changes in mortality and fertility to past and likely future trends on availability of such kin. The proportion of people aged 60 with a mother alive will more than double between those born in 1911 and 1970, and the figure will increase for at least the next 30 years. While there are increasing concerns about the availability of informal care for elderly people from children in the next quarter century or so, in fact we conclude that a higher proportion of elderly people are likely to have a surviving child than for any generation ever born in Britain, and will have more than any foreseeable future cohort.     

The codon 72 polymorphic variants of p53 have markedly different apoptotic potential

The gene TP53, encoding p53, has a common sequence polymorphism that results in either proline or arginine at amino-acid position 72. This polymorphism occurs in the proline-rich domain of p53, which is necessary for the protein to fully induce apoptosis. We found that in cell lines containing inducible versions of alleles encoding the Pro72 and Arg72 variants, and in cells with endogenous p53, the Arg72 variant induces apoptosis markedly better than does the Pro72 variant. Our data indicate that at least one source of this enhanced apoptotic potential is the greater ability of the Arg72 variant to localize to the mitochondria; this localization is accompanied by release of cytochrome c into the cytosol. These data indicate that the two polymorphic variants of p53 are functionally distinct, and these differences may influence cancer risk or treatment.     

The effect of central nervous system stimulation on plasma erythropoietin levels in rhesus monkeys

Zusammenfassung Elektrische Reizung der Nuclei supraoptici und preoptici hypothalami, ebenso der eminentia mediana hatte eine signifikante Erhöhung des Plasma Erythropoietins zur Folge, nicht aber bei Reizung der Nuclei mammillaria hypothalami und commissura anterior. Es wird der hypothalamische Einfluss auf die Erythropoiese kurz erörtert.     

A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice

Public health measures have successfully identified and contained outbreaks of the severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), but concerns remain over the possibility of future recurrences. Finding a vaccine for this virus therefore remains a high priority. Here, we show that a DNA vaccine encoding the spike (S) glycoprotein of the SARS-CoV induces T cell and neutralizing antibody responses, as well as protective immunity, in a mouse model. Alternative forms of S were analysed by DNA immunization. These expression vectors induced robust immune responses mediated by CD4 and CD8 cells, as well as significant antibody titres, measured by enzyme-linked immunosorbent assay. Moreover, antibody responses in mice vaccinated with an expression vector encoding a form of S that includes its transmembrane domain elicited neutralizing antibodies. Viral replication was reduced by more than six orders of magnitude in the lungs of mice vaccinated with these S plasmid DNA expression vectors, and protection was mediated by a humoral but not a T-cell-dependent immune mechanism. Gene-based vaccination for the SARS-CoV elicits effective immune responses that generate protective immunity in an animal model.     

Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein

Neurofibrillary tangles (NFT) composed of the microtubule-associated protein tau are prominent in Alzheimer disease (AD), Pick disease, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Mutations in the gene (Mtapt) encoding tau protein cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), thereby proving that tau dysfunction can directly result in neurodegeneration. Expression of human tau containing the most common FTDP-17 mutation (P301L) results in motor and behavioural deficits in transgenic mice, with age- and gene-dose-dependent development of NFT. This phenotype occurred as early as 6.5 months in hemizygous and 4.5 months in homozygous animals. NFT and Pick-body-like neuronal lesions occurred in the amygdala, septal nuclei, pre-optic nuclei, hypothalamus, midbrain, pons, medulla, deep cerebellar nuclei and spinal cord, with tau-immunoreactive pre-tangles in the cortex, hippocampus and basal ganglia. Areas with the most NFT had reactive gliosis. Spinal cord had axonal spheroids, anterior horn cell loss and axonal degeneration in anterior spinal roots. We also saw peripheral neuropathy and skeletal muscle with neurogenic atrophy. Brain and spinal cord contained insoluble tau that co-migrated with insoluble tau from AD and FTDP-17 brains. The phenotype of mice expressing P301L mutant tau mimics features of human tauopathies and provides a model for investigating the pathogenesis of diseases with NFT.