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A key feature of immune functional impairment with age is the progressive involution of thymic tissue responsible for naive T cell production. In this study, we identify two major phases of thymic epithelial cell (TEC) loss during aging: a block in mature TEC differentiation from the pool of immature precursors, occurring at the onset of puberty, followed by impaired bipotent TEC progenitor differentiation and depletion of Sca-1lo cTEC and mTEC lineage-specific precursors. We reveal that an increase in follistatin production by aging TECs contributes to their own demise. TEC loss occurs primarily through the antagonism of activin A signaling, which we show is required for TEC maturation and acts in dissonance to BMP4, which promotes the maintenance of TEC progenitors. These results support a model in which an imbalance of activin A and BMP4 signaling underpins the degeneration of postnatal TEC maintenance during aging, and its reversal enables the transient replenishment of mature TECs.

Human testicular germ cell tumours commonly feature abundant infiltrating immune cells, most previously identified as T cells and macrophages. But what consequences come along with these changes within the tumour environment? In our study, in addition to immune-morphological analysis, the cytokine microenvironment of testicular cancers has been surveyed for the first time, performing RT-qPCR on human testicular biopsy samples. The results reveal significantly increased expression of pro-inflammatory cytokines in cancer samples relative to healthy tissue, as well as cytokines associated with B cells, whose presence can further be confirmed by immunohistochemistry. These ex vivo results suggest an exceptional involvement of B cells and pro-inflammatory cytokines in the immunopathology of testicular cancer. Having identified the significantly different cytokine profile associated with testis cancer, which cell type might be mainly responsible for its establishment? For addressing this question, an in vitro model was developed to assess the interactions and single contributions of immune and testicular cancer cells to the tumor environment in more detail. TCam2 cells (human seminoma-derived cell line) were co-cultured with human peripheral blood mononuclear cells (PBMCs) to interrogate responses to their co-localization. Data from nine independent experiments using PBMCs from eight different donors indicate that seminoma cell growth is unaffected by direct or indirect contact with PBMCs, at least in short-term. However, cytokine expression profiles of cell-to-cell co-cultured TCam2 cells show significantly increased mRNA levels of pro-inflammatory cytokines IL-1beta, IFN-gamma, TNF-alpha, TGF-beta1 and CCL-5 compared to mono-cultured controls. These outcomes resemble the ex vivo data and highlight the potential of neoplastic human germ cells to promote immune cell infiltration and to actively shape their cytokine microenvironment. Furthermore, three co-culture setups wi

Human testicular germ cell tumours commonly feature abundant infiltrating immune cells, most previously identified as T cells and macrophages. But what consequences come along with these changes within the tumour environment? In our study, in addition to immune-morphological analysis, the cytokine microenvironment of testicular cancers has been surveyed for the first time, performing RT-qPCR on human testicular biopsy samples. The results reveal significantly increased expression of pro-inflammatory cytokines in cancer samples relative to healthy tissue, as well as cytokines associated with B cells, whose presence can further be confirmed by immunohistochemistry. These ex vivo results suggest an exceptional involvement of B cells and pro-inflammatory cytokines in the immunopathology of testicular cancer. Having identified the significantly different cytokine profile associated with testis cancer, which cell type might be mainly responsible for its establishment? For addressing this question, an in vitro model was developed to assess the interactions and single contributions of immune and testicular cancer cells to the tumor environment in more detail. TCam2 cells (human seminoma-derived cell line) were co-cultured with human peripheral blood mononuclear cells (PBMCs) to interrogate responses to their co-localization. Data from nine independent experiments using PBMCs from eight different donors indicate that seminoma cell growth is unaffected by direct or indirect contact with PBMCs, at least in short-term. However, cytokine expression profiles of cell-to-cell co-cultured TCam2 cells show significantly increased mRNA levels of pro-inflammatory cytokines IL-1beta, IFN-gamma, TNF-alpha, TGF-beta1 and CCL-5 compared to mono-cultured controls. These outcomes resemble the ex vivo data and highlight the potential of neoplastic human germ cells to promote immune cell infiltration and to actively shape their cytokine microenvironment. Furthermore, three co-culture setups wi

In the adult rat testis, macrophages belong to one of two subsets differentiated by expression or lack of expression of the resident macrophage surface antigen recognized by monoclonal antibody ED2. Local regulation of the testicular macrophage subsets was investigated in normal and 4-wk experimentally cryptorchid adult rats with and without s.c. testosterone implants (T-implants). Macrophage subsets ED2+ (resident-type) and ED2- (monocyte-like) were identified immunohistochemically and counted in perfusion-fixed frozen testis sections. Depletion of the spermatogenic cells by cryptorchidism had no effect on testicular macrophage numbers. Inhibition of Leydig cell and seminiferous tubule function by low-dose (3 cm) T-implants caused a 40% reduction in ED2+ resident macrophages in both scrotal and abdominal testes. High-dose (24 cm) T-implants, which inhibit Leydig cell function while maintaining normal seminiferous tubule function, also reduced the number of resident macrophages by approximately 40%, although this reduction was at least partially prevented in the abdominal testes. In the scrotal testis only, the ED2- monocyte/macrophage subset was significantly reduced in number by low-dose, but not highdose, T-implants. The concentration of the Leydig cell-secreted cytokine macrophage-migration inhibitory factor (MIF) in testicular fluid was reduced by cryptorchidism, but not by the T-implants. When data from all experimental groups were combined, ED2+ resident macrophage numbers showed a significant positive correlation with parameters of Leydig cell function (serum LH and testicular testosterone levels) but a negative correlation with MIF levels. This study indicates that Leydig cells regulate testicular macrophage numbers directly, rather than via an effect upon the seminiferous epithelium, in the adult rat testis. The data also suggest that testosterone and MIF play only a minor role, if any, in this regulation.

In the adult rat testis, macrophages belong to one of two subsets differentiated by expression or lack of expression of the resident macrophage surface antigen recognized by monoclonal antibody ED2. Local regulation of the testicular macrophage subsets was investigated in normal and 4-wk experimentally cryptorchid adult rats with and without s.c. testosterone implants (T-implants). Macrophage subsets ED2+ (resident-type) and ED2- (monocyte-like) were identified immunohistochemically and counted in perfusion-fixed frozen testis sections. Depletion of the spermatogenic cells by cryptorchidism had no effect on testicular macrophage numbers. Inhibition of Leydig cell and seminiferous tubule function by low-dose (3 cm) T-implants caused a 40% reduction in ED2+ resident macrophages in both scrotal and abdominal testes. High-dose (24 cm) T-implants, which inhibit Leydig cell function while maintaining normal seminiferous tubule function, also reduced the number of resident macrophages by approximately 40%, although this reduction was at least partially prevented in the abdominal testes. In the scrotal testis only, the ED2- monocyte/macrophage subset was significantly reduced in number by low-dose, but not highdose, T-implants. The concentration of the Leydig cell-secreted cytokine macrophage-migration inhibitory factor (MIF) in testicular fluid was reduced by cryptorchidism, but not by the T-implants. When data from all experimental groups were combined, ED2+ resident macrophage numbers showed a significant positive correlation with parameters of Leydig cell function (serum LH and testicular testosterone levels) but a negative correlation with MIF levels. This study indicates that Leydig cells regulate testicular macrophage numbers directly, rather than via an effect upon the seminiferous epithelium, in the adult rat testis. The data also suggest that testosterone and MIF play only a minor role, if any, in this regulation.

The EU Water Framework Directive (WFD) is novel because it integrates water quality, water resources, physical habitat and, to some extent, flooding for all surface and groundwaters and takes forward river basin management. However, the WFD does not explicitly mention risks posed by climate change to the achievement of its environmental objectives. This is despite the fact that the time-scale for the implementation process and achieving particular objectives extends into the 2020s, when climate models project changes in average temperature and precipitation. This paper begins by reviewing the latest UK climate change scenarios and the wider policy and science context of the WFD. We then examine the potential risks of climate change to key phases of the River Basin Management process that underpin the WFD (such as characterisation of river basins and their water bodies, risk assessments to identify pressures and impacts, programmes of measures (POMs) options appraisal, monitoring and modelling, policy and management activities). Despite these risks the WFD could link new policy and participative mechanisms (being established for River Basin Management Plans) to the emerging framework of national and regional climate change adaptation policy. The risks are identified with a view to informing policy opportunities, objective setting, adaptation strategies and the research agenda. Key knowledge gaps have already been identified during the implementation of the WFD, such as the links between hydromorphology and ecosystem status, but the overarching importance of linking climate change to these considerations needs to be highlighted. The next generation of (probabilistic) climate change scenarios will present new opportunities and challenges for risk analysis and policy-making.

The EU Water Framework Directive (WFD) is novel because it integrates water quality, water resources, physical habitat and, to some extent, flooding for all surface and groundwaters and takes forward river basin management. However, the WFD does not explicitly mention risks posed by climate change to the achievement of its environmental objectives. This is despite the fact that the time-scale for the implementation process and achieving particular objectives extends into the 2020s, when climate models project changes in average temperature and precipitation. This paper begins by reviewing the latest UK climate change scenarios and the wider policy and science context of the WFD. We then examine the potential risks of climate change to key phases of the River Basin Management process that underpin the WFD (such as characterisation of river basins and their water bodies, risk assessments to identify pressures and impacts, programmes of measures (POMs) options appraisal, monitoring and modelling, policy and management activities). Despite these risks the WFD could link new policy and participative mechanisms (being established for River Basin Management Plans) to the emerging framework of national and regional climate change adaptation policy. The risks are identified with a view to informing policy opportunities, objective setting, adaptation strategies and the research agenda. Key knowledge gaps have already been identified during the implementation of the WFD, such as the links between hydromorphology and ecosystem status, but the overarching importance of linking climate change to these considerations needs to be highlighted. The next generation of (probabilistic) climate change scenarios will present new opportunities and challenges for risk analysis and policy-making.