Super massive black holes at the centres of galaxies can cycle through periods of activity and quiescence. Characterising the duty cycle of active galactic nuclei (AGN) is crucial for understanding... Show moreSuper massive black holes at the centres of galaxies can cycle through periods of activity and quiescence. Characterising the duty cycle of active galactic nuclei (AGN) is crucial for understanding the impact of the energy they release on the host galaxy. For radio AGN, this can be done by identifying dying (remnant) and restarted radio galaxies from their radio spectral properties. Using the combination of the images at 1400 MHz produced by Apertif, the new phased-array feed receiver installed on the Westerbork Synthesis Radio Telescope, and images at 150 MHz provided by LOFAR, we have derived resolved spectral index images (at a resolution of similar to 15 arcsec) for all the sources within an approximately 6 deg(2) area of the Lockman Hole region. In this way, we were able to select 15 extended radio sources with emission (partly or entirely) characterised by extremely steep spectral indices (steeper than 1.2). These objects represent cases of radio sources in the remnant or the restarted phases of their life cycle. Our findings confirm that these objects are not as rare as previously thought, suggesting a relatively fast cycle. They also show a variety of properties that can be relevant for modelling the evolution of radio galaxies. For example, the restarted activity can occur while the remnant structure from a previous phase of activity is still visible. This provides constraints on the duration of the "off" (dying) phase. In extended remnants with ultra-steep spectra at low frequencies, the activity likely stopped a few hundred megayears ago, and they correspond to the older tail of the age distribution of radio galaxies, in agreement with the results of simulations of radio source evolution. We find remnant radio sources with a variety of structures (from double-lobed to amorphous), possibly suggesting different types of progenitors. The present work sets the stage for exploiting the powerful tool of low-frequency spectral index studies of extended sources by taking advantage of the large areas common to the LOFAR and the Apertif surveys. Show less
Morganti, R.; Oosterloo, T.A.; Brienza, M.; Jurlin, N.; Prandoni, I.; Orrù, E.; ... ; Ziemke, J. 2021
A detailed analyses of HPV-specific immunity was performed in a large group of patients with HPV-induced cervical cancer (CxCa) in relation to HLA-types and prognostic factors. Patients were HLA... Show moreA detailed analyses of HPV-specific immunity was performed in a large group of patients with HPV-induced cervical cancer (CxCa) in relation to HLA-types and prognostic factors. Patients were HLA-typed and HPV16/18-specific T-cell immunity was assessed by proliferation assay and cytometric bead array using freshly isolated PBMC and by phenotypic analysis of HPV-specific T cells. The results were analyzed in relation to known disease-related HLA-types (DR7, DR13, DR15/DQ06), invasion-depth and size of tumor, lymph node (LN) status and disease free survival. In total 119 HLA-typed patients with CxCa were analyzed. Patients expressing the HLA-DR13 haplotype were underrepresented as compared to the Dutch population (p = 0.014), whereas HLA-DR7 was overrepresented in patients with HPV16+ CxCa (p = 0.006). In 29 of 94 patients (31%) from whom blood could be tested, a proliferative response to HPV16/18 was detected, which was associated with increased numbers of HPV-specific CD4+CD25+ (activated) T cells (p = 0.03) and HPV-specific CD4+CD25+FoxP3-positive T cells (p = 0.04). The presence of both FoxP3-positive and negative HPV-specific CD4+CD25+ T cells was significantly correlated (p = 0.01). Interestingly, the detection of HPV-specific proliferation was associated with invasion depth (p = 0.020) but not with HLA type, tumor size nor LN status. Moreover, the detection of HPV-specific immunity was associated with an improved disease free survival (p = 0.04) in patients with deeply infiltrating tumors. In conclusion, HPV-specific proliferative T-cell response, comprising higher percentages of HPV-specific CD25+ and CD25+FoxP3-positive CD4+T cells, are more frequently detected in patients with deep infiltrating CxCa tumors and associated with an improved survival. Show less
Piersma, S.J.; Hulst, J.M. van der; Kwappenberg, K.M.C.; Goedemans, R.; Minne, C.E. van der; Burg, S.H. van der 2010
Control and termination of infection with Influenza A virus is associated with increased IL-10 production in mouse models. Notably, IL-10 can be produced by Treg. Therefore, we investigated whether... Show moreControl and termination of infection with Influenza A virus is associated with increased IL-10 production in mouse models. Notably, IL-10 can be produced by Treg. Therefore, we investigated whether the population of IL-10-producing influenza-specific CD4(+) T cells comprised Treg as they are potent suppressors of the adaptive immune response. Influenza-specific IL-10-producing T cells were detected in all human donors displaying influenza-specific immunity. Isolation of Matrix 1 protein-specific IL-10-producing T-cell clones revealed that a substantial proportion of these T-cell clones displayed the capacity to suppress effector cells, functionally identifying them as Treg. Both FOXP3(+) and FOXP3(-) CD4(+) Treg were isolated and all were able to exert their suppressive capacity when stimulated with cognate antigen, including influenza virus-infected cells. In vitro suppression was not mediated by IL-10 but involved interference with the IL-2 axis. The isolated Treg suppressed amongst others the IL-2 production of influenza-specific T-helper cells as well as partially prevented the upregulation of the high-affinity IL-2 receptor on CD8 effector cells. So far the induction of virus-specific Treg has only been studied in the context of chronic viral infections. This study demonstrates that virus-specific Treg can also be induced by viruses that are rapidly cleared in humans. Show less
Welters, M.J.P.; Kenter, G.G.; Steenwijk, P.J.D. van; Lowik, M.J.G.; Berends-van der Meer, D.M.A.; Essahsah, F.; ... ; Burg, S.H. van der 2010
One half of a group of 20 patients with human papillomavirus type 16 (HPV16)-induced vulvar intraepithelial neoplasia grade 3 displayed a complete regression (CR) after therapeutic vaccination with... Show moreOne half of a group of 20 patients with human papillomavirus type 16 (HPV16)-induced vulvar intraepithelial neoplasia grade 3 displayed a complete regression (CR) after therapeutic vaccination with HPV16 E6/E7 synthetic long peptides. Patients with relatively larger lesions generally did not display a CR. To investigate immune correlates of treatment failure, patients were grouped according to median lesion size at study entry, and HPV16-specific immunity was analyzed at different time points by complementary immunological assays. The group of patients with smaller lesions displayed stronger and broader vaccine-prompted HPV16-specific proliferative responses with higher IFN gamma (P = 0.0003) and IL-5 (P < 0.0001) levels than patients with large lesions. Characteristically, this response was accompanied by a distinct peak in cytokine levels after the first vaccination. In contrast, the patient group with larger lesions mounted higher frequencies of HPV16-specific CD4(+)CD25(+)Foxp3(+)T cells (P = 0.005) and displayed a lower HPV16-specific IFN gamma/IL-10 ratio after vaccination (P<0.01). No disparity in T memory immunity to control antigens was found, indicating that the differences in HPV-specific immunity did not reflect general immune failure. We observed a strong correlation between a defined set of vaccine-prompted specific immune responses and the clinical efficacy of therapeutic vaccination. Notably, a high ratio of HPV16-specific vaccine-prompted effector T cells to HPV16-specificCD4(+)CD25(+)Foxp3(+)T cells was predictive of clinical success. Foxp3(+)T cells have been associated previously with impaired immunity in malignancies. Here we demonstrate that the vaccine-prompted level of this population is associated with early treatment failure. Show less
Steenwijk, P.J.D. van; Heusinkveld, M.; Ramwadhdoebe, T.H.; Lowik, M.J.; Hulst, J.M. van der; Goedemans, R.; ... ; Burg, S.H. van der 2010
The diversity and extent of the local tumor-specific T-cell response in a given individual is largely unknown. We have performed an in-depth study of the local T-cell repertoire in a selected group... Show moreThe diversity and extent of the local tumor-specific T-cell response in a given individual is largely unknown. We have performed an in-depth study of the local T-cell repertoire in a selected group of patients with cervical cancer, by systematic analyses of the proportion, breadth, and polarization of human papillomavirus (HPV) E6/E7-specific T cells within the total population of tumor-infiltrating lymphocytes (TIL) and tumor-draining lymph node cells (TDLNC). Isolated T cells were stimulated with sets of overlapping E6 and E7 peptides and analyzed by multiparameter flow cytometry with respect to activation, cytokine production, and T-cell receptor V beta usage. HPV-specific CD4+ and CD8+ T-cell responses were detected in TIL and TDLNC and their relative contribution varied between <1% and 66% of all T cells. In general, these HPV-specific responses were surprisingly broad, aimed at multiple E6 and E7 epitopes and involved multiple dominant and subdominant T-cell receptor V beta s per single peptide-epitope. In most patients, only few IFN gamma-producing T cells were found and the amount of IFN gamma produced was low, suggesting that these are poised T cells, rendered functionally inactive within the tumor environment. Importantly, stimulation of the TIL and TDLNC with cognate antigen in the presence of commonly used Toll-like receptor ligands significantly enhanced the effector T-cell function. In conclusion, our study suggests that within a given patient with HPV-specific immunity many different tumor-specific CD4+ and CD8+ T cells are locally present and poised for action. This vast existing local T-cell population is awaiting proper stimulation and can be exploited for the immunotherapy of cancer. Cancer Res; 70(7); 2707-17. (C) 2010 AACR. Show less
Hummel, E.; Hulst, J.M. van der; Keel, W.C.; Kennicutt jr., R.C. 1987
