The role of the CD8 co-receptor in CD8+ T-cell activation

CD8+ T-cells are essential for the immune control of pathogens and the natural eradication of cancer. CD8+ T-cells also play a major role in the pathogenesis of autoimmunity and\ud alloreactivity. CD8+ T-cells recognize short peptide fragments (8-13 amino acids) presented at the target cell surface bound to Major Histocompatability Class I (MHCI) molecules. Tcell antigen recognition is unique in nature because it involves the binding of a single ligand (peptide–MHC [pMHC]) by two receptors (TCR and CD8). The CD8 glycoprotein, which serves as the coreceptor on MHCI-restricted T-cells, acts to enhance the antigen sensitivity of T-cells by binding to a largely invariant region of MHCI at a site distinct from the TCR docking platform. CD8 has been shown to have multiple roles including enhancing effects on early T-cell activation events and also in controlling the level of T-cell cross-reactivity. The pMHCI/CD8 interaction is classified as having a very weak binding affinity and very fast kinetics. I discovered that this low solution binding affinity is essential in maintaining homeostasis as dramatically increasing the strength of this interaction resulted in total loss of T-cell specificity and activation independent of TCR engagement. This led me to examine the possibility that anti-CD8 antibodies could also bypass the normal requirements for T-cell activation. I identified one specific clonotype of antibody capable of this phenomenon but simultaneously discovered multiple effector phenotypes of other anti-CD8 antibodies. These included both enhancing and inhibitory effects on pMHCI tetramer binding and CD8+ T-cell activation. Subsequently, I explored the possibility of using these inhibitory anti-CD8 antibodies to block T-cell function in systems which are highly dependent on CD8 such as autoreactive CD8+ T-cells. I demonstrated that targeting CD8 can be used as a strategy to block autoreactive CD8+ T-cell activation in the absence of any effect on pathogen specific immunity. This highlights a novel therapeutic strategy that warrants further investigation. Finally, I demonstrated that CD8 can alter the functional avidity of a CD8+ T-cell for its agonists and act to re-arrange the relative potencies of each of its potential agonists, a novel “focussing mechanism” for CD8 in T cell activation. These results provide new insight to the biological role of CD8 in T-cells and even predict a novel mechanism for CD8 in controlling T-cell function. My results also highlight the potential of targeting CD8 for immunotherapeutic design in autoimmune disorders

Cytokine-mediated induction and regulation of tissue damage during cytomegalovirus infection

Human cytomegalovirus (HCMV) is a β-herpesvirus with high sero-prevalence within the human population. Primary HCMV infection and life-long carriage are typically asymptomatic. However, HCMV is implicated in exacerbation of chronic conditions and associated damage in individuals with intact immune systems. Furthermore, HCMV is a significant cause of morbidity and mortality in the immunologically immature and immune-compromised where disease is associated with tissue damage. Infection-induced inflammation, including robust cytokine responses, is a key component of pathologies associated with many viruses. Despite encoding a large number of immune-evasion genes, HCMV also triggers the induction of inflammatory cytokine responses during infection. Thus, understanding how cytokines contribute to CMV-induced pathologies and the mechanisms through which they are regulated may inform clinical management of disease. Herein, we discuss our current understanding based on clinical observation and in vivo modeling of disease of the role that cytokines play in CMV pathogenesis. Specifically, in the context of the different tissues and organs in which CMV replicates, we give a broad overview of the beneficial and adverse effects that cytokines have during infection and describe how cytokine-mediated tissue damage is regulated. We discuss the implications of findings derived from mice and humans for therapeutic intervention strategies and our understanding of how host genetics may influence the outcome of CMV infections

Increasing uptake of hepatitis C virus infection case- finding, testing, and treatment in primary care: evaluation of the HepCATT (Hepatitis C Assessment Through to Treatment) trial

Background Hepatitis C virus (HCV) infection is a key cause of liver disease but can be cured in more than 95% of patients. Around 70 000 people in England may have undiagnosed HCV infection and many more will not have been treated. Interventions to increase case-finding in primary care are likely to be cost-effective; however, evidence of effective interventions is lacking. The Hepatitis C Assessment Through to Treatment (HepCATT) trial assessed whether a complex intervention in primary care could increase case-finding, testing, and treatment of HCV.Aim To investigate the feasibility and acceptability of the HepCATT intervention.Design and setting A qualitative study with primary care practice staff from practices in the south west of England taking part in the HepCATT trial.Method Semi-structured interviews were carried out with GPs, nurses, and practice staff to ascertain their views of the HepCATT intervention at least 1 month after implementing the intervention in their practice. Normalisation process theory, which outlines the social processes involved in intervention implementation, informed thematic data analysis.Results Participants appreciated the HepCATT intervention for increasing knowledge and awareness of HCV. Although some initial technical difficulties were reported, participants saw the benefits of using the audit tool to systematically identify patients with HCV infection risk factors and found it straightforward to use. Participants valued the opportunity to discuss HCV testing with patients, especially those who may not have been previously aware of HCV risk. Future implementation should consider fully integrating software systems and additional resources to screen patient lists and conduct tests.Conclusion When supported by a complex intervention, primary care can play a crucial role in identifying and caring for patients with HCV infection, to help stem the HCV epidemic, and prevent HCV-related illnes

Challenges in Scaling Up Greenhouse Gas Fluxes: Experience From the UK Greenhouse Gas Emissions and Feedbacks Program

The role of greenhouse gases (GHGs) in global climate change is now well recognized and there is a clear need to measure emissions and verify the efficacy of mitigation measures. To this end, reliable estimates are needed of the GHG balance at the national scale and over long time periods, but these estimates are difficult to make accurately. Because measurement techniques are generally restricted to relatively small spatial and temporal scales, there is a fundamental problem in translating these into long-term estimates on a regional scale. The key challenge lies in spatial and temporal upscaling of short-term, point observations to estimate large-scale annual totals, and quantify the uncertainty associated with this upscaling. Here, we review some approaches to this problem and synthesize the work in the recent UK Greenhouse Gas Emissions and Feedbacks Program, which was designed to identify and address these challenges. Approaches to the scaling problem included: instrumentation developments which mean that near-continuous data sets can be produced with larger spatial coverage; geostatistical methods which address the problem of extrapolating to larger domains, using spatial information in the data; more rigorous statistical methods which characterize the uncertainty in extrapolating to longer time scales; analytical approaches to estimating model aggregation error; enhanced estimates of C flux measurement error; and novel uses of remote sensing data to calibrate process models for generating probabilistic regional C flux estimates

Interferon lambda is required for interferon gamma-expressing NK cell responses but does not afford antiviral protection during acute and persistent murine cytomegalovirus infection

Interferon lambda (IFNλ) is a group of cytokines that belong to the IL-10 family. They exhibit antiviral activities against certain viruses during infection of the liver and mucosal tissues. Here we report that IFNλ restricts in vitro replication of the β-herpesvirus murine cytomegalovirus (mCMV). However, IFNλR1-deficient (Ifnλr1-/-) mice were not preferentially susceptible to mCMV infection in vivo during acute infection after systemic or mucosal challenge, or during virus persistence in the mucosa. Instead, our studies revealed that IFNλ influences NK cell responses during mCMV infection. Ifnλr1-/- mice exhibited defective development of conventional interferon-gamma (IFNγ)-expressing NK cells in the spleen during mCMV infection whereas accumulation of granzyme B-expressing NK cells was unaltered. In vitro, development of splenic IFNγ+ NK cells following stimulation with IL-12 or, to a lesser extent, IL-18 was abrogated by IFNλR1-deficiency. Thus, IFNλ regulates NK cell responses during mCMV infection and restricts virus replication in vitro but is redundant in the control of acute and persistent mCMV replication within mucosal and non-mucosal tissues

Ethnobotanical survey of medicinal plants used in the management of cancer in Uganda

Introduction: Patients with cancer in Africa embrace the use of herbal medicine more than anywhere else in the world. This study identified and documented medicinal plant species used to manage cancer in ten (10) districts of Uganda. Methods: An ethnobotanical survey was conducted between October 2021 and January 2022. In total, 18 (out of 55) traditional medicine practitioners (TMPs) having more than 10 years of experience in managing patients with cancer were interviewed using a semi-structured questionnaire. Data were analysed using descriptive statistics. The Relative frequency of citation (RFC) and Family importance value (FIV) indices were also computed. Results: We identified 121 plant species, belonging to 55 families, with the most common families being the Fabaceae (20 species, FIV = 0.119), Asteraceae (13 species, FIV = 0.131), and Euphorbiaceae (eight species, FIV = 0.079). The plant parts most commonly used were leaves (39.3%) and roots (12.9%). The most frequently cited plants were: Hoslundia opposita Vahl (RFC = 0.44), followed by Aspilia africana (Pers.) C.D. Adams (RFC = 0.33), Spathodea nilotica Seem (RFC = 0.33), Annona muricata L. (RFC = 0.33, Prunus africana (Hook.f.) Kalkman (RFC = 0.28), Acacia hockii De Wild (RFC = 0.28), Bidens pilosa L. (RFC = 0.28), and Carica papaya L (RFC = 0.22). The most common method of plant preparation and administration was the decoction (69.2%) and oral (86.7%) route, respectively. Conclusions: Although most plants used by TMPs have the potential to generate leads for chemo-preventive cancer medicines, they remain unexplored. This study provides a lead to explore the potential of traditionally used plants for the management of cancer through pre-clinical and clinical research

Optimal CD8+ T-cell memory formation following subcutaneous cytomegalovirus infection requires virus replication but not early dendritic cell responses

Cytomegalovirus (CMV) induction of large frequencies of highly functional memory T-cells has attracted much interest in the utility of CMV-based vaccine vectors, with exciting preclinical data obtained in models of infectious diseases and cancer. However, pathogenesis of human CMV (HCMV) remains a concern. Attenuated CMV-based vectors, such as replication- or spread-deficient viruses potentially offer an alternative to fully replicating vectors. However, it is not well-understood how CMV attenuation impacts vector immunogenicity, in particularly when administered via relevant routes of immunization such as the skin. Herein we used the murine cytomegalovirus (MCMV) model to investigate the impact of vector attenuation on T-cell memory formation following subcutaneous administration. We found that the spread deficient virus (ΔgL-MCMV) was impaired in its ability to induce memory CD8+ T-cells reactive to some (M38, IE1) but not all (IE3) viral antigens. Impaired memory T-cell development was associated with a preferential and pronounced loss of polyfunctional (IFN-γ+ TNF-α+) T-cells and also reduced accumulation of TCF1+ T-cells, and was not rescued by increasing the dose of replication-defective MCMV. Finally, whilst vector attenuation reduced dendritic cell (DC) recruitment to skin-draining lymph nodes, systematic depletion of multiple DC subsets during acute subcutaneous MCMV infection had a negligible impact on T-cell memory formation, implying that attenuated responses induced by replication-deficient vectors were likely not a consequence of impaired initial DC activation. Thus, overall, these data imply that the choice of antigen and/or cloning strategy of exogenous antigen in combination with the route of immunization may influence the ability of attenuated CMV vectors to induce robust functional T-cell memory

Evidence-based opportunities for out-scaling climate-smart agriculture in East Africa

Climate-smart agriculture (CSA) is being widely promoted as a solution for food insecurity and climate change adaptation in food systems of sub-Saharan Africa, while simultaneously reducing the rate of greenhouse gas emissions. Governments throughout Africa are writing policies and programs to promote CSA practices despite uncertainty about the ability for practices to meet the triple CSA objectives of CSA. We conducted a systematic review of 175 peer-reviewed and grey literature studies, to gauge the impact of over seventy potential CSA practices on CSA outcomes in Tanzania and Uganda. Using a total of 6,342 observations, we found that practice impacts were highly context (i.e. farming system and location) specific. Nevertheless, practice effect across CSA outcomes generally agreed in direction. While our results suggest that CSA is indeed possible, lack of mitigation data precludes a more conclusive statement. Furthermore, the inclusion of potential adoption rates changes the potential of CSA practices to achieve benefits at scale. Given the uncertainty and variable impacts of practices across regions and outcomes, it is critical for decision makers to prioritize practices based on their desired outcomes and local context

The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors

Acknowledgments The authors wish to acknowledge the NIH-sponsored Mutant Mouse Regional Resource Center (MMRRC) National System as the source of genetically-altered mice (C57BL/6-Clec4etm1.1Cfg/Mmucd 031936-UCD) for use in this study. The mice were produced and deposited to the MMRRC by the Consortium for Functional Glycomics supported by the National Institute of General Medical Sciences (GM62116). We would like to thank Catherine Neiseryan and Ann Kift-Morgan for cell sorting. We would like to thank Wales Gene Park for providing computer resources that assisted this research. Funding: SJO was funded by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 099953/Z/12/Z) and by a Wellcome Trust ISSF Cross-Disciplinary Award. LCD is supported by a Henry Wellcome Trust Postdoctoral Fellowship (103973/Z/14/Z). CL is supported by a Kidney Research UK/MedImmune Joint Fellowship Award (PDF_006_20151127). GDB is funded by a Wellcome Trust Investigator Award (102705) and the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1). IRH is supported by a Wellcome Trust Senior Research Fellowship (207503/Z/17/Z). PRT is supported by a Wellcome Trust Investigator Award (107964/Z/15/Z) and the UK Dementia Research Institute. Funding URLs: https://wellcome.ac.uk/ https://royalsociety.org/ https://www.kidneyresearchuk.org/ https://mrc.ukri.org/ https://ukdri.ac.uk/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability: All relevant data apart from RNAseq files are within the manuscript and its Supporting Information files. RNAseq data files are available from ArrayExpress (https://www.ebi.ac.uk/arrayexpress/), (accession number E-MTAB-8030).Peer reviewedPublisher PD