Immunology

#Immunotherapy | What do #Cancer-Specific #Tcells ‘See’ 🤔 | Vicky Brentville Lindy Durrant & Co. take a Look down the #Immunooncology Microscope in British…

21 December 2022 In a recent publication, scientists made a big advancement in their knowledge of how inflammation i

Immune responses are governed by signals from the tissue microenvironment, and in addition to biochemical signals, mechanical cues and forces arising from the tissue, its extracellular matrix and its constituent cells shape immune cell function. Indeed, changes in biophysical properties of tissue alter the mechanical signals experienced by cells in many disease conditions, in inflammatory states and in the context of ageing. These mechanical cues are converted into biochemical signals through the process of mechanotransduction, and multiple pathways of mechanotransduction have been identified in immune cells. Such pathways impact important cellular functions including cell activation, cytokine production, metabolism, proliferation and trafficking. Changes in tissue mechanics may also represent a new form of ‘danger signal’ that alerts the innate and adaptive immune systems to the possibility of injury or infection. Tissue mechanics can change temporally during an infection or inflammatory response, offering a novel layer of dynamic immune regulation. Here, we review the emerging field of mechanoimmunology, focusing on how mechanical cues at the scale of the tissue environment regulate immune cell behaviours to initiate, propagate and resolve the immune response. This Review considers how the biophysical properties of a tissue are able to shape immune cell function through the process of mechanotransduction. There are multiple mechanotransduction pathways that operate in immune cells and the authors highlight these and the emerging field of mechanoimmunology.

Inborn errors of immunity (IEI) are diseases caused by genetic mutations that affect the immune system’s ability to fight pathogens, cope with the microbiota or regulate autoimmunity and inflammation. More than 500 IEI have been described and many are life-threatening and require curative therapy. Allogeneic haematopoietic stem cell transplantation is an increasingly effective curative strategy, and autologous transplantation of gene-modified haematopoietic stem and progenitor cells is also a treatment option. Gene therapy was first successfully used to restore T cell development in patients with severe combined immunodeficiency, with ex vivo engineered gammaretroviral vectors enabling the sustained correction of T cell immunodeficiency more than 20 years later. The generation of safer and more potent vectors has increased the efficacy and application of this therapy to other IEI, such as Wiskott–Aldrich syndrome and chronic granulomatous disease. Nevertheless, gene therapy based on gene addition has some limitations, the greatest of which is the lack of a physiological gene expression control. This Perspective summarizes the journey of the past 25 years that has led to the successful use of gene therapy for IEI and discusses the next steps for the field. In this Perspective, Alain Fischer reflects on the development of gene therapy for patients with inborn errors of immunity. He discusses the challenges the field has faced as well as the progress seen in the past 25 years.

Labeling of the CCS using systemic mCntn2-800. To assess the feasibility of labeling the CCS in vivo, we conjugated IRDye800CW NHS ester, an NIR dye already in clinical use (10), to a commercially available polyclonal antibody directed against Cntn2, an extracellular marker previously shown to be...

Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are debilitating, clinically heterogeneous and of unknown molecular etiology. A transcriptome-wide investigation was performed in 165 acutely infected hospitalized individuals who were followed clinically into the post-acute period. Distinct gene expression signatures of post-acute sequelae were already present in whole blood during acute infection, with innate and adaptive immune cells implicated in different symptoms. Two clusters of sequelae exhibited divergent plasma-cell-associated gene expression patterns. In one cluster, sequelae associated with higher expression of immunoglobulin-related genes in an anti-spike antibody titer-dependent manner. In the other, sequelae associated independently of these titers with lower expression of immunoglobulin-related genes, indicating lower non-specific antibody production in individuals with these sequelae. This relationship between lower total immunoglobulins and sequelae was validated in an external cohort. Altogether, multiple etiologies of post-acute sequelae were already detectable during SARS-CoV-2 infection, directly linking these sequelae with the acute host response to the virus and providing early insights into their development. Transcriptomic analyses of acute phase whole blood from a large cohort of patients with COVID-19 identify molecular determinants of post-infection long-term sequelae.

Host immunity to infection with SARS-CoV-2 is highly variable, dictating diverse clinical outcomes ranging from asymptomatic to severe disease and death. We previously reported reduced type I interferon in severe COVID-19 patients preceded clinical worsening. Further studies identified genetic mutations in loci of the TLR3- or TLR7-dependent interferon-I pathways, or neutralizing interferon-I autoantibodies as risk factors for development of COVID-19 pneumonia. Here we show in patient cohorts with different severities of COVID-19, that baseline plasma interferon α measures differ according to the immunoassay used, timing of sampling, the interferon α subtype measured, and the presence of autoantibodies. We also show a consistently reduced induction of interferon-I proteins in hospitalized COVID-19 patients upon immune stimulation, that is not associated with detectable neutralizing autoantibodies against interferon α or interferon ω. Intracellular proteomic analysis shows increased monocyte numbers in hospitalized COVID-19 patients but impaired interferon-I response after stimulation. We confirm this by ex vivo whole blood stimulation with interferon-I which induces transcriptomic responses associated with inflammation in hospitalized COVID-19 patients, that is not seen in controls or non-hospitalized moderate cases. These results may explain the dichotomy of the poor clinical response to interferon-I based treatments in late stage COVID-19, despite the importance of interferon-I in early acute infection and may guide alternative therapeutic strategies. The interferon response has been shown to be linked to severity of SARS-CoV-2 infection and is an essential component of the immune response to COVID-19. Here the authors stratify patients according to COVID-19 severity and asses the interferon response showing defective responses in severe infection and highlight the importance of assay variables and confounding factors that impact the detection of interferon.

Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification
of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency
Treatment Consortium’s (PIDTC’s) prospective and retrospective studies of SCID.

Macrophages are critical regulators of immunity and play key roles in a range of biological
and pathological processes. This review provides a conceptual framework for improving
our understanding of the contributions of macrophages of different origins to physiological
and disease states.

The twenty-first century has witnessed major developments in the field of extracellular vesicle (EV) research, including significant steps towards defining standard criteria for the separation and detection of EVs. The recent recognition that EVs have the potential to function as biomarkers or as therapeutic tools has attracted even greater attention to their study. With this progress in mind, an updated comprehensive overview of the roles of EVs in the immune system is timely. This Review summarizes the roles of EVs in basic processes of innate and adaptive immunity, including inflammation, antigen presentation, and the development and activation of B cells and T cells. It also highlights key progress related to deciphering the roles of EVs in antimicrobial defence and in allergic, autoimmune and antitumour immune responses. It ends with a focus on the relevance of EVs to immunotherapy and vaccination, drawing attention to ongoing or recently completed clinical trials that aim to harness the therapeutic potential of EVs. Extracellular vesicles (EVs) are increasingly recognized as having ubiquitous roles in the immune system. This Review focuses on the progress made in the field in the past 5 years, including the roles of EVs in innate and adaptive immunity and their potential use in diagnosis and therapy.