Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity

Autoimmune diseases are thought to result from imbalances in normal immune physiology and regulation. Here, we show that autoimmune disease susceptibility and resistance alleles on mouse chromosome 3 (Idd3) correlate with differential expression of the key immunoregulatory cytokine interleukin-2 (IL-2). In order to test directly that an approximately twofold reduction in IL-2 underpins the Idd3-linked destabilization of immune homeostasis, we show that engineered haplodeficiency of Il2 gene expression not only reduces T cell IL-2 production by twofold but also mimics the autoimmune dysregulatory effects of the naturally occurring susceptibility alleles of Il2. Reduced IL-2 production achieved by either genetic mechanism correlates with reduced function of CD4(+) CD25(+) regulatory T cells, which are critical for maintaining immune homeostasis.     

The DNA sequence and biological annotation of human chromosome 1

The reference sequence for each human chromosome provides the framework for understanding genome function, variation and evolution. Here we report the finished sequence and biological annotation of human chromosome 1. Chromosome 1 is gene-dense, with 3,141 genes and 991 pseudogenes, and many coding sequences overlap. Rearrangements and mutations of chromosome 1 are prevalent in cancer and many other diseases. Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, and also in regions where no function is evident. Fine-scale recombination occurs in hotspots of varying intensity along the sequence, and is enriched near genes. These and other studies of human biology and disease encoded within chromosome 1 are made possible with the highly accurate annotated sequence, as part of the completed set of chromosome sequences that comprise the reference human genome.     

Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity

Protective T-cell memory has long been thought to reside in blood and lymph nodes, but recently the concept of immune memory in peripheral tissues mediated by resident memory T (T(RM)) cells has been proposed. Here we show in mice that localized vaccinia virus (VACV) skin infection generates long-lived non-recirculating CD8(+) skin T(RM) cells that reside within the entire skin. These skin T(RM) cells are potent effector cells, and are superior to circulating central memory T (T(CM)) cells at providing rapid long-term protection against cutaneous re-infection. We find that CD8(+) T cells are rapidly recruited to skin after acute VACV infection. CD8(+) T-cell recruitment to skin is independent of CD4(+) T cells and interferon-γ, but requires the expression of E- and P-selectin ligands by CD8(+) T cells. Using parabiotic mice, we further show that circulating CD8(+) T(CM) and CD8(+) skin T(RM) cells are both generated after skin infection; however, CD8(+) T(CM) cells recirculate between blood and lymph nodes whereas T(RM) cells remain in the skin. Cutaneous CD8(+) T(RM) cells produce effector cytokines and persist for at least 6 months after infection. Mice with CD8(+) skin T(RM) cells rapidly cleared a subsequent re-infection with VACV whereas mice with circulating T(CM) but no skin T(RM) cells showed greatly impaired viral clearance, indicating that T(RM) cells provide superior protection. Finally, we show that T(RM) cells generated as a result of localized VACV skin infection reside not only in the site of infection, but also populate the entire skin surface and remain present for many months. Repeated re-infections lead to progressive accumulation of highly protective T(RM) cells in non-involved skin. These findings have important implications for our understanding of protective immune memory at epithelial interfaces with the environment, and suggest novel strategies for vaccines that protect against tissue tropic organisms.     

Continental collision slowing due to viscous mantle lithosphere rather than topography

Because the inertia of tectonic plates is negligible, plate velocities result from the balance of forces acting at plate margins and along their base. Observations of past plate motion derived from marine magnetic anomalies provide evidence of how continental deformation may contribute to plate driving forces. A decrease in convergence rate at the inception of continental collision is expected because of the greater buoyancy of continental than oceanic lithosphere, but post-collisional rates are less well understood. Slowing of convergence has generally been attributed to the development of high topography that further resists convergent motion; however, the role of deforming continental mantle lithosphere on plate motions has not previously been considered. Here I show that the rate of India's penetration into Eurasia has decreased exponentially since their collision. The exponential decrease in convergence rate suggests that contractional strain across Tibet has been constant throughout the collision at a rate of 7.03?×?10(-16)?s(-1), which matches the current rate. A constant bulk strain rate of the orogen suggests that convergent motion is resisted by constant average stress (constant force) applied to a relatively uniform layer or interface at depth. This finding follows new evidence that the mantle lithosphere beneath Tibet is intact, which supports the interpretation that the long-term strain history of Tibet reflects deformation of the mantle lithosphere. Under conditions of constant stress and strength, the deforming continental lithosphere creates a type of viscous resistance that affects plate motion irrespective of how topography evolved.     

Global warming preceded by increasing carbon dioxide concentrations during the last deglaciation

The covariation of carbon dioxide (CO(2)) concentration and temperature in Antarctic ice-core records suggests a close link between CO(2) and climate during the Pleistocene ice ages. The role and relative importance of CO(2) in producing these climate changes remains unclear, however, in part because the ice-core deuterium record reflects local rather than global temperature. Here we construct a record of global surface temperature from 80 proxy records and show that temperature is correlated with and generally lags CO(2) during the last (that is, the most recent) deglaciation. Differences between the respective temperature changes of the Northern Hemisphere and Southern Hemisphere parallel variations in the strength of the Atlantic meridional overturning circulation recorded in marine sediments. These observations, together with transient global climate model simulations, support the conclusion that an antiphased hemispheric temperature response to ocean circulation changes superimposed on globally in-phase warming driven by increasing CO(2) concentrations is an explanation for much of the temperature change at the end of the most recent ice age.     

Chromosomal rearrangements maintain a polymorphic supergene controlling butterfly mimicry

Supergenes are tight clusters of loci that facilitate the co-segregation of adaptive variation, providing integrated control of complex adaptive phenotypes. Polymorphic supergenes, in which specific combinations of traits are maintained within a single population, were first described for 'pin' and 'thrum' floral types in Primula and Fagopyrum, but classic examples are also found in insect mimicry and snail morphology. Understanding the evolutionary mechanisms that generate these co-adapted gene sets, as well as the mode of limiting the production of unfit recombinant forms, remains a substantial challenge. Here we show that individual wing-pattern morphs in the polymorphic mimetic butterfly Heliconius numata are associated with different genomic rearrangements at the supergene locus P. These rearrangements tighten the genetic linkage between at least two colour-pattern loci that are known to recombine in closely related species, with complete suppression of recombination being observed in experimental crosses across a 400-kilobase interval containing at least 18 genes. In natural populations, notable patterns of linkage disequilibrium (LD) are observed across the entire P region. The resulting divergent haplotype clades and inversion breakpoints are found in complete association with wing-pattern morphs. Our results indicate that allelic combinations at known wing-patterning loci have become locked together in a polymorphic rearrangement at the P locus, forming a supergene that acts as a simple switch between complex adaptive phenotypes found in sympatry. These findings highlight how genomic rearrangements can have a central role in the coexistence of adaptive phenotypes involving several genes acting in concert, by locally limiting recombination and gene flow.     

First record of Climacia californica (Neuroptera: Sisyridae) and its host sponge, Ephydatia mulleri (Porifera: spongillidae), from Idaho with water quality relationships

The spongillafly, Climacia californica Chandler, and its sponge host, Ephydatia mulleri (Lieberkuhn), are reported from the state of Idaho for the first time. Climacia californica has not previously been reported from E. mulleri . Collections were made in the Burley – Twin Falls area, and detailed water quality data are provided for the first time for spongillafly larvae. The water quality data also expand the known tolerance limits of E. mulleri for water temperature, conductivity, pH, hardness, silica, and residue.         

First record of pygmy rabbits ( Brachylagus idahoensis ) in Wyoming

Pygmy rabbits are reported for the first time in southwestern Wyoming. The range for this species is thus extended 240 km and 145 km from the nearest records in Idaho and Utah, respectively.