Dendritic Cells Crosspresent Antigens from Live B16 Cells More Efficiently than from Apoptotic Cells and Protect from Melanoma in a Therapeutic Model

Dendritic cells (DC) are able to elicit anti-tumoral CD8+ T cell responses by cross-presenting exogenous antigens in association with major histocompatibility complex (MHC) class I molecules. Therefore they are crucial actors in cell-based cancer immunotherapy. Although apoptotic cells are usually considered to be the best source of antigens, live cells are also able to provide antigens for cross-presentation by DC. We have recently shown that prophylactic immunotherapy by DC after capture of antigens from live B16 melanoma cells induced strong CD8+ T-cell responses and protection against a lethal tumor challenge in vivo in C57Bl/6 mice. Here, we showed that DC cross-presenting antigens from live B16 cells can also inhibit melanoma lung dissemination in a therapeutic protocol in mice. DC were first incubated with live tumor cells for antigen uptake and processing, then purified and irradiated for safety prior to injection. This treatment induced stronger tumor-specific CD8+ T-cell responses than treatment by DC cross-presenting antigens from apoptotic cells. Apoptotic B16 cells induced more IL-10 secretion by DC than live B16 cells. They underwent strong native antigen degradation and led to the expression of fewer MHC class I/epitope complexes on the surface of DC than live cells. Therefore, the possibility to use live cells as sources of tumor antigens must be taken into account to improve the efficiency of cancer immunotherapy

Front Immunol

HIV-2 infection is characterized by low viremia and slow disease progression as compared to HIV-1 infection. Circulating CD14++CD16+ monocytes were found to accumulate and CD11c+ conventional dendritic cells (cDC) to be depleted in a Portuguese cohort of people living with HIV-2 (PLWHIV-2), compared to blood bank healthy donors (HD). We studied more precisely classical monocytes; CD16+ inflammatory (intermediate, non-classical and slan+ monocytes, known to accumulate during viremic HIV-1 infection); cDC1, important for cross-presentation, and cDC2, both depleted during HIV-1 infection. We analyzed by flow cytometry these PBMC subsets from Paris area residents: 29 asymptomatic, untreated PLWHIV-2 from the IMMUNOVIR-2 study, part of the ANRS-CO5 HIV-2 cohort: 19 long-term non-progressors (LTNP; infection ≥8 years, undetectable viral load, stable CD4 counts≥500/μL; 17 of West-African origin -WA), and 10 non-LTNP (P; progressive infection; 9 WA); and 30 age-and sex-matched controls: 16 blood bank HD with unknown geographical origin, and 10 HD of WA origin (GeoHD). We measured plasma bacterial translocation markers by ELISA. Non-classical monocyte counts were higher in GeoHD than in HD (54 vs. 32 cells/μL, p = 0.0002). Slan+ monocyte counts were twice as high in GeoHD than in HD (WA: 28 vs. 13 cells/μL, p = 0.0002). Thus cell counts were compared only between participants of WA origin. They were similar in LTNP, P and GeoHD, indicating that there were no HIV-2 related differences. cDC counts did not show major differences between the groups. Interestingly, inflammatory monocyte counts correlated with plasma sCD14 and LBP only in PLWHIV-2, especially LTNP, and not in GeoHD. In conclusion, in LTNP PLWHIV-2, inflammatory monocyte counts correlated with LBP or sCD14 plasma levels, indicating a potential innate immune response to subclinical bacterial translocation. As GeoHD had higher inflammatory monocyte counts than HD, our data also show that specific controls are important to refine innate immunity studies

Paleoclimate Implications for Human-Made Climate Change

Paleoclimate data help us assess climate sensitivity and potential human-made climate effects. We conclude that Earth in the warmest interglacial periods of the past million years was less than 1{\deg}C warmer than in the Holocene. Polar warmth in these interglacials and in the Pliocene does not imply that a substantial cushion remains between today's climate and dangerous warming, but rather that Earth is poised to experience strong amplifying polar feedbacks in response to moderate global warming. Thus goals to limit human-made warming to 2{\deg}C are not sufficient - they are prescriptions for disaster. Ice sheet disintegration is nonlinear, spurred by amplifying feedbacks. We suggest that ice sheet mass loss, if warming continues unabated, will be characterized better by a doubling time for mass loss rate than by a linear trend. Satellite gravity data, though too brief to be conclusive, are consistent with a doubling time of 10 years or less, implying the possibility of multi-meter sea level rise this century. Observed accelerating ice sheet mass loss supports our conclusion that Earth's temperature now exceeds the mean Holocene value. Rapid reduction of fossil fuel emissions is required for humanity to succeed in preserving a planet resembling the one on which civilization developed.Comment: 32 pages, 9 figures; final version accepted for publication in "Climate Change at the Eve of the Second Decade of the Century: Inferences from Paleoclimate and Regional Aspects: Proceedings of Milutin Milankovitch 130th Anniversary Symposium" (eds. Berger, Mesinger and Sijaci

Climate change patterns in Amazonia and biodiversity

Precise characterization of hydroclimate variability in Amazonia on various timescales is critical to understanding the link between climate change and biodiversity. Here we present absolute-dated speleothem oxygen isotope records that characterize hydroclimate variation in western and eastern Amazonia over the past 250 and 20 ka, respectively. Although our records demonstrate the coherent millennial-scale precipitation variability across tropical-subtropical South America, the orbital-scale precipitation variability between western and eastern Amazonia exhibits a quasi-dipole pattern. During the last glacial period, our records imply a modest increase in precipitation amount in western Amazonia but a significant drying in eastern Amazonia, suggesting that higher biodiversity in western Amazonia, contrary to 'Refugia Hypothesis', is maintained under relatively stable climatic conditions. In contrast, the glacial-interglacial climatic perturbations might have been instances of loss rather than gain in biodiversity in eastern Amazonia, where forests may have been more susceptible to fragmentation in response to larger swings in hydroclimate. © 2013 Macmillan Publishers Limited. All rights reserved

Holocene sea ice variability driven by wind and polynya efficiency in the Ross Sea

The causes of the recent increase in Antarctic sea ice extent, characterised by large regional contrasts and decadal variations, remain unclear. In the Ross Sea, where such a sea ice increase is reported, 50% of the sea ice is produced within wind-sustained latent-heat polynyas. Combining information from marine diatom records and sea salt sodium and water isotope ice core records, we here document contrasting patterns in sea ice variations between coastal and open sea areas in Western Ross Sea over the current interglacial period. Since about 3600 years before present, an increase in the efficiency of regional latent-heat polynyas resulted in more coastal sea ice, while sea ice extent decreased overall. These past changes coincide with remarkable optima or minima in the abundances of penguins, silverfish and seal remains, confirming the high sensitivity of marine ecosystems to environmental and especially coastal sea ice conditions

Cross-talk between iNKT cells and CD8 T cells in the spleen requires the IL-4/CCL17 axis for the generation of short-lived effector cells

Mounting an effective immune response relies critically on the coordinated interactions between adaptive and innate compartments. How and where immune cells from these different compartments interact is still poorly understood. Here, we demonstrate that the cross-talk between invariant natural killer T cells (iNKT) and CD8(+) T cells in the spleen, essential for initiating productive immune responses, is biphasic and occurs at 2 distinct sites. Codelivery of antigen and adjuvant to antigen-presenting cells results in: 1) initial short-lived interactions (0 to 6 h), between CD8(+) T cells, dendritic cells (DCs), and iNKT cells recruited outside the white pulp; 2) followed by longlasting contacts (12 to 24 h) between iNKT cells, DCs, and CD8(+) T cells occurring in a 3-way interaction profile within the white pulp. Both CXCR3 and CCR4 are essential to orchestrate this highly dynamic process and play nonredundant in T cell memory generation. While CXCR3 promotes memory T cells, CCR4 supports short-lived effector cell generation. We believe our work provides insights into the initiation of T cell responses in the spleen and their consequences for T cell differentiation

Apoptotic cell capture by DCs induces unexpectedly robust autologous CD4(+) T-cell responses

Item does not contain fulltextApoptotic cells represent an important source of self-antigens and their engulfment by dendritic cells (DCs) is usually considered to be related to tolerance induction. We report here an unexpectedly high level of human CD4(+) T-cell proliferation induced by autologous DCs loaded with autologous apoptotic cells, due to the activation of more than 10% of naive CD4(+) T cells. This proliferation is not due to an increase in the costimulatory capacity of DCs, but is dependent on apoptotic cell-associated material processed through an endo-lysosomal pathway and presented on DC MHC class II molecules. Autologous CD4(+) T cells stimulated with apoptotic cell-loaded DCs exhibit suppressive capacities. However, in the presence of bacterial lipopolysaccharide, apoptotic cell-loaded DCs induce the generation of IL-17-producing cells. Thus, apoptotic cell engulfment by DCs may lead to increased autologous responses, initially generating CD4(+) T cells with suppressive capacities able to differentiate into Th17 cells in the presence of a bacterial danger signal such as LPS

Lake highstands on the Altiplano (Tropical Andes) contemporaneous with Heinrich 1 and the Younger Dryas: new insights from ^(14)C, U-Th dating and δ^(18)O of carbonates

This study provides new geochronological and stable isotope constraints on Late Pleistocene fluctuations in lake level that occurred in the closed-watershed of the Central Altiplano between ~25 and ~12 ka. U-series isochrons and ^(14)C ages from carbonates are used to confirm and refine the previous chronology published (Placzek et al., 2006b). Our new data support three successive lake highstands during the Late Pleistocene: (i) the Lake Sajsi cycle, from ~25 to 19 ka, that culminated at 3670 m at about 22 ka, almost synchronously with the global last glacial maximum, (ii) the Lake Tauca cycle, that lasted from 18 to 14.5 ka and was characterized by the highest water level, reached at least 3770 m from 16.5 to 15 ka, (iii) the Lake Coipasa cycle, from 12.5 to 11.9 ka, that reached an elevation of ~3700 m, 42 m above the elevation of the Salar de Uyuni (3658 m). These high amplitude lake level fluctuations are in phase with the cold-warm oscillations that occurred in the North Atlantic and Greenland during the Late Pleistocene (Heinrich 1, Bølling-Allerød, Younger Dryas). Such temporal coincidence supports the hypothesis that wet events recorded in the Central Altiplano are controlled by the northesouth displacement of the Inter Tropical Convergence Zone resulting from changes in the meridional temperature gradient. Finally, the oxygen isotope ratios measured in these lacustrine carbonates allows for calculation of the δ^(18)O value of paleolake waters. Estimates of water δ^(18)O (V-SMOW) are -2.8 ± 0.7‰ for Lake Tauca and -1.6 ± 0.9‰ for Lake Coipasa. These data are used to constrain changes in lake hydrology and can be interpreted to indicate that the proportion of precipitation arising from local water recycling was less than 50%

Conventional Dendritic Cells and Slan+ Monocytes During HIV-2 Infection

HIV-2 infection is characterized by low viremia and slow disease progression as compared to HIV-1 infection. Circulating CD14++CD16+ monocytes were found to accumulate and CD11c+ conventional dendritic cells (cDC) to be depleted in a Portuguese cohort of people living with HIV-2 (PLWHIV-2), compared to blood bank healthy donors (HD). We studied more precisely classical monocytes; CD16+ inflammatory (intermediate, non-classical and slan+ monocytes, known to accumulate during viremic HIV-1 infection); cDC1, important for cross-presentation, and cDC2, both depleted during HIV-1 infection. We analyzed by flow cytometry these PBMC subsets from Paris area residents: 29 asymptomatic, untreated PLWHIV-2 from the IMMUNOVIR-2 study, part of the ANRS-CO5 HIV-2 cohort: 19 long-term non-progressors (LTNP; infection ≥8 years, undetectable viral load, stable CD4 counts≥500/μL; 17 of West-African origin -WA), and 10 non-LTNP (P; progressive infection; 9 WA); and 30 age-and sex-matched controls: 16 blood bank HD with unknown geographical origin, and 10 HD of WA origin (GeoHD). We measured plasma bacterial translocation markers by ELISA. Non-classical monocyte counts were higher in GeoHD than in HD (54 vs. 32 cells/μL, p = 0.0002). Slan+ monocyte counts were twice as high in GeoHD than in HD (WA: 28 vs. 13 cells/μL, p = 0.0002). Thus cell counts were compared only between participants of WA origin. They were similar in LTNP, P and GeoHD, indicating that there were no HIV-2 related differences. cDC counts did not show major differences between the groups. Interestingly, inflammatory monocyte counts correlated with plasma sCD14 and LBP only in PLWHIV-2, especially LTNP, and not in GeoHD. In conclusion, in LTNP PLWHIV-2, inflammatory monocyte counts correlated with LBP or sCD14 plasma levels, indicating a potential innate immune response to subclinical bacterial translocation. As GeoHD had higher inflammatory monocyte counts than HD, our data also show that specific controls are important to refine innate immunity studies