Two Host Factors Regulate Persistence of H7a-Specific T Cells Injected in Tumor-Bearing Mice

BACKGROUND: Injection of CD8 T cells primed against immunodominant minor histocompatibility antigens (MiHA) such as H7(a) can eradicate leukemia and solid tumors. To understand why MiHA-targeted T cells have such a potent antitumor effect it is essential to evaluate their in vivo behavior. In the present work, we therefore addressed two specific questions: what is the proliferative dynamics of H7(a)-specifc T cells in tumors, and do H7(a)-specific T cells persist long-term after adoptive transfer? METHODOLOGY/PRINCIPAL FINDINGS: By day 3 after adoptive transfer, we observed a selective infiltration of melanomas by anti-H7(a) T cells. Over the next five days, anti-H7(a) T cells expanded massively in the tumor but not in the spleen. Thus, by day 8 after injection, anti-H7(a) T cells in the tumor had undergone more cell divisions than those in the spleen. These data strongly suggest that anti-H7(a) T cells proliferate preferentially and extensively in the tumors. We also found that two host factors regulated long-term persistence of anti-H7(a) memory T cells: thymic function and expression of H7(a) by host cells. On day 100, anti-H7(a) memory T cells were abundant in euthymic H7(a)-negative (B10.H7(b)) mice, present in low numbers in thymectomized H7(a)-positive (B10) hosts, and undetectable in euthymic H7(a)-positive recipients. CONCLUSIONS/SIGNIFICANCE: Although in general the tumor environment is not propitious to T-cell invasion and expansion, the present work shows that this limitation may be overcome by adoptive transfer of primed CD8 T cells targeted to an immunodominant MiHA (here H7(a)). At least in some cases, prolonged persistence of adoptively transferred T cells may be valuable for prevention of late cancer relapse in adoptive hosts. Our findings therefore suggest that it may be advantageous to target MiHAs with a restricted tissue distribution in order to promote persistence of memory T cells and thereby minimize the risk of cancer recurrence

Differences in access to Emergency Paediatric Intensive Care and care during Transport (DEPICT): study protocol for a mixed methods study

Introduction Following centralisation of UK paediatric intensive care, specialist retrieval teams were established who travel to general hospitals to stabilise and transport sick children to regional paediatric intensive care units (PICUs). There is national variation among these PICU retrieval teams (PICRTs) in terms of how quickly they reach the patient’s bedside and in the care provided during transport. The impact of these variations on clinical outcomes and the experience of stakeholders (patients, families and healthcare staff) is however unknown. The primary objective of this study is to address this evidence gap. Methods and analysis This mixed-methods project involves the following: (1) retrospective analysis of linked data from routine clinical audits (2014–2016) to assess the impact of service variations on 30-day mortality and other secondary clinical outcomes; (2) a prospective questionnaire study conducted at 24 PICUs and 9 associated PICRTs in England and Wales over a 12-month period in 2018 to collect experience data from parents of transported children as well as qualitative analysis of in-depth interviews with a purposive sample of patients, parents and staff to assess the impact of service variations on patient/family experience; (3) health economic evaluation analysing transport service costs (and other associated costs) against lives saved and longer term measurements of quality of life at 12 months in transported children and (4) mathematical modelling evaluating the costs and potential impact of different service configurations. A final work stream involves a series of stakeholder workshops to synthesise study findings and generate recommendations. Ethics and dissemination The study has been reviewed and approved by the Health Research Authority, ref: 2 18 569. Study results will be actively disseminated through peer-reviewed journals, conference presentations, social media, print and broadcast media, the internet and stakeholder workshops

The COTUR project: remote sensing of offshore turbulence for wind energy application

The paper presents the measurement strategy and data set collected during the COTUR (COherence of TURbulence with lidars) campaign. This field experiment took place from February 2019 to April 2020 on the southwestern coast of Norway. The coherence quantifies the spatial correlation of eddies and is little known in the marine atmospheric boundary layer. The study was motivated by the need to better characterize the lateral coherence, which partly governs the dynamic wind load on multi-megawatt offshore wind turbines. During the COTUR campaign, the coherence was studied using land-based remote sensing technology. The instrument setup consisted of three long-range scanning Doppler wind lidars, one Doppler wind lidar profiler and one passive microwave radiometer. Both the WindScanner software and LidarPlanner software were used jointly to simultaneously orient the three scanner heads into the mean wind direction, which was provided by the lidar wind profiler. The radiometer instrument complemented these measurements by providing temperature and humidity profiles in the atmospheric boundary layer. The scanning beams were pointed slightly upwards to record turbulence characteristics both within and above the surface layer, providing further insight on the applicability of surface-layer scaling to model the turbulent wind load on offshore wind turbines. The preliminary results show limited variations of the lateral coherence with the scanning distance. A slight increase in the identified Davenport decay coefficient with the height is partly due to the limited pointing accuracy of the instruments. These results underline the importance of achieving pointing errors under 0.1∘ to study properly the lateral coherence of turbulence at scanning distances of several kilometres.publishedVersio

Functional Redundancy of Langerhans Cells and Langerin+ Dermal Dendritic Cells in Contact Hypersensitivity

The relative roles of Langerhans cells (LC), dermal dendritic cells (DC), and, in particular, the recently discovered Langerin+ dermal DC subset in the induction and control of contact hypersensitivity (CHS) responses remain controversial. Using an inducible mouse model, in which LC and other Langerin+ DC can be depleted by injection of diphtheria toxin, we previously reported impaired transport of topically applied antigen to draining lymph nodes and reduced CHS in the absence of all Langerin+ skin DC. In this study, we demonstrate that mice with a selective depletion of LC exhibit attenuated CHS only upon sensitization with a low hapten dose but not with a high hapten dose. In contrast, when painting a higher concentration of hapten onto the skin, which leads to increased antigen dissemination into the dermis, CHS is still diminished in mice lacking all Langerin+ skin DC. Taken together, these data suggest that the magnitude of a CHS reaction depends on the number of skin DC, which have access to the hapten, rather than on the presence or absence of a particular skin DC population. LC and (Langerin+) dermal DC thus seem to have a redundant function in regulating CHS.Journal of Investigative Dermatology advance online publication, 12 August 2010; doi:10.1038/jid.2010.223