T cell control of SARS-CoV-2: When, which, and where?

Efficient immune protection against viruses such as SARS-CoV-2 requires the coordinated activity of innate immunity, B and T cells. Accumulating data point to a critical role for T cells not only in the clearance of established infection, but also for aborting viral replication independently of humoral immunity. Here we review the evidence supporting the contribution of antiviral T cells and consider which of their qualitative features favour efficient control of infection. We highlight how studies of SARS-CoV-2 and other coronaviridae in animals and humans have provided important lessons on the optimal timing (When), functionality and specificity (Which), and location (Where) of antiviral T cells. We discuss the clinical implications, particularly for the development of next-generation vaccines, and emphasise areas requiring further study

Viral vectored hepatitis C virus vaccines generate pan-genotypic T cell responses to conserved subdominant epitopes

Background: Viral genetic variability presents a major challenge to the development of a prophylactic hepatitis C virus (HCV) vaccine. A promising HCV vaccine using chimpanzee adenoviral vectors (ChAd) encoding a genotype (gt) 1b non-structural protein (ChAd-Gt1b-NS) generated high magnitude T cell responses. However, these T cells showed reduced cross-recognition of dominant epitope variants and the vaccine has recently been shown to be ineffective at preventing chronic HCV. To address the challenge of viral diversity, we developed ChAd vaccines encoding HCV genomic sequences that are conserved between all major HCV genotypes and adjuvanted by truncated shark invariant chain (sIitr). / Methods: Age-matched female mice were immunised intramuscularly with ChAd (108 infectious units) encoding gt-1 and -3 (ChAd-Gt1/3) or gt-1 to -6 (ChAd-Gt1-6) conserved segments spanning the HCV proteome, or gt-1b (ChAd-Gt1b-NS control), with immunogenicity assessed 14-days post-vaccination. / Results: Conserved segment vaccines, ChAd-Gt1/3 and ChAd-Gt1-6, generated high-magnitude, broad, and functional CD4+ and CD8+ T cell responses. Compared to the ChAd-Gt1b-NS vaccine, these vaccines generated significantly greater responses against conserved non-gt-1 antigens, including conserved subdominant epitopes that were not targeted by ChAd-Gt1b-NS. Epitopes targeted by the conserved segment HCV vaccine induced T cells, displayed 96.6% mean sequence homology between all HCV subtypes (100% sequence homology for the majority of genotype-1, -2, -4 sequences and 94% sequence homology for gt-3, -6, -7, and -8) in contrast to 85.1% mean sequence homology for epitopes targeted by ChAd-Gt1b-NS induced T cells. The addition of truncated shark invariant chain (sIitr) increased the magnitude, breadth, and cross-reactivity of the T cell response. / Conclusions: We have demonstrated that genetically adjuvanted ChAd vectored HCV T cell vaccines encoding genetic sequences conserved between genotypes are immunogenic, activating T cells that target subdominant conserved HCV epitopes. These pre-clinical studies support the use of conserved segment HCV T cell vaccines in human clinical trials

Characterizing Hepatitis C Virus–Specific CD4+ T Cells Following Viral‐Vectored Vaccination, Directly Acting Antivirals, and Spontaneous Viral Cure

BACKGROUND AND AIMS: Induction of functional helper CD4+ T cells is the hallmark of a protective immune response against hepatitis C virus (HCV), associated with spontaneous viral clearance. Heterologous prime/boost viral vectored vaccination has demonstrated induction of broad and polyfunctional HCV-specific CD8+ T cells in healthy volunteers; however, much less is known about CD4+ T-cell subsets following vaccination. APPROACH AND RESULTS: We analyzed HCV-specific CD4+ T-cell populations using major histocompatibility complex class II tetramers in volunteers undergoing HCV vaccination with recombinant HCV adenoviral/modified vaccinia Ankara viral vectors. Peptide-specific T-cell responses were tracked over time, and functional (proliferation and cytokine secretion) and phenotypic (cell surface and intranuclear) markers were assessed using flow cytometry. These were compared to CD4+ responses in 10 human leukocyte antigen-matched persons with HCV spontaneous resolution and 21 chronically infected patients treated with directly acting antiviral (DAA) therapy. Vaccination induced tetramer-positive CD4+ T cells that were highest 1-4 weeks after boosting (mean, 0.06%). Similar frequencies were obtained for those tracked following spontaneous resolution of disease (mean, 0.04%). In addition, the cell-surface phenotype (CD28, CD127) memory subset markers and intranuclear transcription factors, as well as functional capacity of peptide-specific CD4+ T-cell responses characterized after vaccination, are comparable to those following spontaneous viral resolution. In contrast, helper responses in chronic infection were infrequently detected and poorly functional and did not consistently recover following HCV cure. CONCLUSIONS: Helper CD4+ T-cell phenotype and function following HCV viral vectored vaccination resembles "protective memory" that is observed following spontaneous clearance of HCV. DAA cure does not promote resurrection of exhausted CD4+ T-cell memory in chronic infection

Formation of radiatively cooled, supersonically rotating, plasma flows in Z-pinch experiments: Towards the development of an experimental platform to study accretion disk physics in the laboratory

International audienc

Formation and Structure of a Current Sheet in Pulsed-Power Driven Magnetic Reconnection Experiments

We describe magnetic reconnection experiments using a new, pulsed-power driven experimental platform in which the inflows are super-sonic but sub-Alfv\'enic.The intrinsically magnetised plasma flows are long lasting, producing a well-defined reconnection layer that persists over many hydrodynamic time scales.The layer is diagnosed using a suite of high resolution laser based diagnostics which provide measurements of the electron density, reconnecting magnetic field, inflow and outflow velocities and the electron and ion temperatures.Using these measurements we observe a balance between the power flow into and out of the layer, and we find that the heating rates for the electrons and ions are significantly in excess of the classical predictions. The formation of plasmoids is observed in laser interferometry and optical self-emission, and the magnetic O-point structure of these plasmoids is confirmed using magnetic probes.Comment: 14 pages, 12 figures. Accepted for publication in Physics of Plasma

Characterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma

Immunotherapy is now the standard of care for advanced hepatocellular carcinoma (HCC), yet many patients fail to respond. A major unmet goal is the boosting of T-cells with both strong HCC reactivity and the protective advantages of tissue-resident memory T-cells (TRM). Here, we show that higher intratumoural frequencies of γδ T-cells, which have potential for HLA-unrestricted tumour reactivity, associate with enhanced HCC patient survival. We demonstrate that γδ T-cells exhibit bona fide tissue-residency in human liver and HCC, with γδTRM showing no egress from hepatic vasculature, persistence for >10 years and superior anti-tumour cytokine production. The Vγ9Vδ2 T-cell subset is selectively depleted in HCC but can efficiently target HCC cell lines sensitised to accumulate isopentenyl-pyrophosphate by the aminobisphosphonate Zoledronic acid. Aminobisphosphonate-based expansion of peripheral Vγ9Vδ2 T-cells recapitulates a TRM phenotype and boosts cytotoxic potential. Thus, our data suggest more universally effective HCC immunotherapy may be achieved by combining aminobisphosphonates to induce Vγ9Vδ2TRM capable of replenishing the depleted pool, with additional intratumoural delivery to sensitise HCC to Vγ9Vδ2TRM-based targeting