Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy

Peptides presented at the cell surface reflect the protein content of the cell; those on HLA class I molecules comprise the critical peptidome elements interacting with CD8 T lymphocytes. We hypothesize that peptidomes from ex vivo tumour samples encompass immunogenic tumour antigens. Here, we uncover >6000 HLA-bound peptides from HLA-A*02+ glioblastoma, of which over 3000 were restricted by HLA-A*02. We prioritized in-depth investigation of 10 glioblastoma-associated antigens based on high expression in tumours, very low or absent expression in healthy tissues, implication in gliomagenesis and immunogenicity. Patients with glioblastoma showed no T cell tolerance to these peptides. Moreover, we demonstrated specific lysis of tumour cells by patients' CD8+ T cells in vitro. In vivo, glioblastoma-specific CD8+ T cells were present at the tumour site. Overall, our data show the physiological relevance of the peptidome approach and provide a critical advance for designing a rational glioblastoma immunotherapy. The peptides identified in our study are currently being tested as a multipeptide vaccine (IMA950) in patients with glioblastom

Receding ice drove parallel expansions in Southern Ocean penguins

International audienceClimate shifts are key drivers of ecosystem change. Despite the critical importance of Antarctica and the Southern Ocean for global climate, the extent of climate-driven ecological change in this region remains controversial. In particular, the biological effects of changing sea ice conditions are poorly understood. We hypothesize that rapid postglacial reductions in sea ice drove biological shifts across multiple widespread Southern Ocean species. We test for demographic shifts driven by climate events over recent millennia by analyzing population genomic datasets spanning 3 penguin genera ( Eudyptes , Pygoscelis , and Aptenodytes ). Demographic analyses for multiple species (macaroni/royal, eastern rockhopper, Adélie, gentoo, king, and emperor) currently inhabiting southern coastlines affected by heavy sea ice conditions during the Last Glacial Maximum (LGM) yielded genetic signatures of near-simultaneous population expansions associated with postglacial warming. Populations of the ice-adapted emperor penguin are inferred to have expanded slightly earlier than those of species requiring ice-free terrain. These concerted high-latitude expansion events contrast with relatively stable or declining demographic histories inferred for 4 penguin species (northern rockhopper, western rockhopper, Fiordland crested, and Snares crested) that apparently persisted throughout the LGM in ice-free habitats. Limited genetic structure detected in all ice-affected species across the vast Southern Ocean may reflect both rapid postglacial colonization of subantarctic and Antarctic shores, in addition to recent genetic exchange among populations. Together, these analyses highlight dramatic, ecosystem-wide responses to past Southern Ocean climate change and suggest potential for further shifts as warming continues

HCV–HIV Coinfection: Simple Messages from a Complex Disease

The authors discuss our current understanding of the immunopathogenesis of HCV-HIV coinfection

Immune Activation and CD8(+) T-Cell Differentiation towards Senescence in HIV-1 Infection

Progress in the fight against the HIV/AIDS epidemic is hindered by our failure to elucidate the precise reasons for the onset of immunodeficiency in HIV-1 infection. Increasing evidence suggests that elevated immune activation is associated with poor outcome in HIV-1 pathogenesis. However, the basis of this association remains unclear. Through ex vivo analysis of virus-specific CD8(+) T-cells and the use of an in vitro model of naïve CD8(+) T-cell priming, we show that the activation level and the differentiation state of T-cells are closely related. Acute HIV-1 infection induces massive activation of CD8(+) T-cells, affecting many cell populations, not only those specific for HIV-1, which results in further differentiation of these cells. HIV disease progression correlates with increased proportions of highly differentiated CD8(+) T-cells, which exhibit characteristics of replicative senescence and probably indicate a decline in T-cell competence of the infected person. The differentiation of CD8(+) and CD4(+) T-cells towards a state of replicative senescence is a natural process. It can be driven by excessive levels of immune stimulation. This may be part of the mechanism through which HIV-1-mediated immune activation exhausts the capacity of the immune system

The African Landscape through Space and Time

It is generally accepted that Cenozoic epeirogeny of the African continent is moderated by convective circulation of the mantle. Nevertheless, the spatial and temporal evolution of Africa's “basin-and-swell” physiography is not well known. Here we show how continental drainage networks can be used to place broad constraints on the pattern of uplift through space and time. First, we assemble an inventory of 710 longitudinal river profiles that includes major tributaries of the 10 largest catchments. River profiles have been jointly inverted to determine the pattern of uplift rate as a function of space and time. Our inverse model assumes that shapes of river profiles are controlled by uplift rate history and modulated by erosional processes, which can be calibrated using independent geologic evidence (e.g., marine terraces, volcanism and thermochronologic data). Our results suggest that modern African topography started to develop ∼30 Myr ago when volcanic swells appeared in North and East Africa. During the last 15–20 Myr, subequatorial Africa was rapidly elevated, culminating in the appearance of three large swells that straddle southern and western coasts. Our results enable patterns of sedimentary flux at major deltas to be predicted and tested. We suggest that the evolution of drainage networks is dominated by rapid upstream advection of signals produced by a changing pattern of regional uplift. An important corollary is that, with careful independent calibration, these networks might act as useful tape recorders of otherwise inaccessible mantle processes. Finally, we note that there are substantial discrepancies between our results and published dynamic topographic predictions

Spoken language processing: piecing together the puzzle

Attempting to understand the fundamental mechanisms underlying spoken language processing, whether it is viewed as behaviour exhibited by human beings or as a faculty simulated by machines, is one of the greatest scientific challenges of our age. Despite tremendous achievements over the past 50 or so years, there is still a long way to go before we reach a comprehensive explanation of human spoken language behaviour and can create a technology with performance approaching or exceeding that of a human being. It is argued that progress is hampered by the fragmentation of the field across many different disciplines, coupled with a failure to create an integrated view of the fundamental mechanisms that underpin one organism's ability to communicate with another. This paper weaves together accounts from a wide variety of different disciplines concerned with the behaviour of living systems - many of them outside the normal realms of spoken language - and compiles them into a new model: PRESENCE (PREdictive SENsorimotor Control and Emulation). It is hoped that the results of this research will provide a sufficient glimpse into the future to give breath to a new generation of research into spoken language processing by mind or machine. (c) 2007 Elsevier B.V. All rights reserved