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.     

Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting

Cancer immunoediting, the process by which the immune system controls tumour outgrowth and shapes tumour immunogenicity, is comprised of three phases: elimination, equilibrium and escape. Although many immune components that participate in this process are known, its underlying mechanisms remain poorly defined. A central tenet of cancer immunoediting is that T-cell recognition of tumour antigens drives the immunological destruction or sculpting of a developing cancer. However, our current understanding of tumour antigens comes largely from analyses of cancers that develop in immunocompetent hosts and thus may have already been edited. Little is known about the antigens expressed in nascent tumour cells, whether they are sufficient to induce protective antitumour immune responses or whether their expression is modulated by the immune system. Here, using massively parallel sequencing, we characterize expressed mutations in highly immunogenic methylcholanthrene-induced sarcomas derived from immunodeficient Rag2(-/-) mice that phenotypically resemble nascent primary tumour cells. Using class I prediction algorithms, we identify mutant spectrin-β2 as a potential rejection antigen of the d42m1 sarcoma and validate this prediction by conventional antigen expression cloning and detection. We also demonstrate that cancer immunoediting of d42m1 occurs via a T-cell-dependent immunoselection process that promotes outgrowth of pre-existing tumour cell clones lacking highly antigenic mutant spectrin-β2 and other potential strong antigens. These results demonstrate that the strong immunogenicity of an unedited tumour can be ascribed to expression of highly antigenic mutant proteins and show that outgrowth of tumour cells that lack these strong antigens via a T-cell-dependent immunoselection process represents one mechanism of cancer immunoediting.     

Novel mutations target distinct subgroups of medulloblastoma

Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.     

Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13

Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.     

A soluble and air-stable organic semiconductor with high electron mobility

Electronic devices based on organic semiconductors offer an attractive alternative to conventional inorganic devices due to potentially lower costs, simpler packaging and compatibility with flexible substrates. As is the case for silicon-based microelectronics, the use of complementary logic elements-requiring n- and p-type semiconductors whose majority charge carriers are electrons and holes, respectively-is expected to be crucial to achieving low-power, high-speed performance. Similarly, the electron-segregating domains of photovoltaic assemblies require both n- and p-type semiconductors. Stable organic p-type semiconductors are known, but practically useful n-type semiconductor materials have proved difficult to develop, reflecting the unfavourable electrochemical properties of known, electron-demanding polymers. Although high electron mobilities have been obtained for organic materials, these values are usually obtained for single crystals at low temperatures, whereas practically useful field-effect transistors (FETs) will have to be made of polycrystalline films that remain functional at room temperature. A few organic n-type semiconductors that can be used in FETs are known, but these suffer from low electron mobility, poor stability in air and/or demanding processing conditions. Here we report a crystallographically engineered naphthalenetetracarboxylic diimide derivative that allows us to fabricate solution-cast n-channel FETs with promising performance at ambient conditions. By integrating our n-channel FETs with solution-deposited p-channel FETs, we are able to produce a complementary inverter circuit whose active layers are deposited entirely from the liquid phase. We expect that other complementary circuit designs can be realized by this approach as well.     

Convergent evolution in mechanical design of lamnid sharks and tunas

The evolution of 'thunniform' body shapes in several different groups of vertebrates, including whales, ichthyosaurs and several species of large pelagic fishes supports the view that physical and hydromechanical demands provided important selection pressures to optimize body design for locomotion during vertebrate evolution. Recognition of morphological similarities between lamnid sharks (the most well known being the great white and the mako) and tunas has led to a general expectation that they also have converged in their functional design; however, no quantitative data exist on the mechanical performance of the locomotor system in lamnid sharks. Here we examine the swimming kinematics, in vivo muscle dynamics and functional morphology of the force-transmission system in a lamnid shark, and show that the evolutionary convergence in body shape and mechanical design between the distantly related lamnids and tunas is much more than skin deep; it extends to the depths of the myotendinous architecture and the mechanical basis for propulsive movements. We demonstrate that not only have lamnids and tunas converged to a much greater extent than previously known, but they have also developed morphological and functional adaptations in their locomotor systems that are unlike virtually all other fishes.     

BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice

Faithful segregation of replicated chromosomes is essential for maintenance of genetic stability and seems to be monitored by several mitotic checkpoints. Various components of these checkpoints have been identified in mammals, but their physiological relevance is largely unknown. Here we show that mutant mice with low levels of the spindle assembly checkpoint protein BubR1 develop progressive aneuploidy along with a variety of progeroid features, including short lifespan, cachectic dwarfism, lordokyphosis, cataracts, loss of subcutaneous fat and impaired wound healing. Graded reduction of BubR1 expression in mouse embryonic fibroblasts causes increased aneuploidy and senescence. Male and female mutant mice have defects in meiotic chromosome segregation and are infertile. Natural aging of wild-type mice is marked by decreased expression of BubR1 in multiple tissues, including testis and ovary. These results suggest a role for BubR1 in regulating aging and infertility.