Explore the vast range of titles available.

The host response to SARS-CoV-2 infection provide insights into both viral pathogenesis and patient management. The host-encoded microRNA (miRNA) response to SARS-CoV-2 infection, however, remains poorly defined. Here we profiled circulating miRNAs from ten COVID-19 patients sampled longitudinally and ten age and gender matched healthy donors. We observed 55 miRNAs that were altered in COVID-19 patients during early-stage disease, with the inflammatory miR-31-5p the most strongly upregulated. Supervised machine learning analysis revealed that a three-miRNA signature (miR-423-5p, miR-23a-3p and miR-195-5p) independently classified COVID-19 cases with an accuracy of 99.9%. In a ferret COVID-19 model, the three-miRNA signature again detected SARS-CoV-2 infection with 99.7% accuracy, and distinguished SARS-CoV-2 infection from influenza A (H1N1) infection and healthy controls with 95% accuracy. Distinct miRNA profiles were also observed in COVID-19 patients requiring oxygenation. This study demonstrates that SARS-CoV-2 infection induces a robust host miRNA response that could improve COVID-19 detection and patient management.

Studies of successive vaccination suggest that immunological memory against past influenza viruses may limit responses to vaccines containing current strains. The impact of memory induced by prior infection is rarely considered and is difficult to ascertain, because infections are often subclinical. This study investigated influenza vaccination among adults from the Ha Nam cohort (Vietnam), who were purposefully selected to include 72 with and 28 without documented influenza A(H3N2) infection during the preceding 9 years (Australian New Zealand Clinical Trials Registry 12621000110886). The primary outcome was the effect of prior influenza A(H3N2) infection on hemagglutinin-inhibiting antibody responses induced by a locally available influenza vaccine administered in November 2016. Baseline and postvaccination sera were titrated against 40 influenza A(H3N2) strains spanning 1968–2018. At each time point (baseline, day 14 and day 280), geometric mean antibody titers against 2008–2018 strains were higher among participants with recent infection (34 (29–40), 187 (154–227) and 86 (72–103)) than among participants without recent infection (19 (17–22), 91 (64–130) and 38 (30–49)). On days 14 and 280, mean titer rises against 2014–2018 strains were 6.1-fold (5.0- to 7.4-fold) and 2.6-fold (2.2- to 3.1-fold) for participants with recent infection versus 4.8-fold (3.5- to 6.7-fold) and 1.9-fold (1.5- to 2.3-fold) for those without. One of 72 vaccinees with recent infection versus 4 of 28 without developed symptomatic A(H3N2) infection in the season after vaccination ( P  = 0.021). The range of A(H3N2) viruses recognized by vaccine-induced antibodies was associated with the prior infection strain. These results suggest that recall of immunological memory induced by prior infection enhances antibody responses to inactivated influenza vaccine and is important to attain protective antibody titers. Recent prior influenza A infection is associated with elevated hemagglutinin-inhibiting antibody responses and greater breadth of reactivity to influenza strains following vaccination, suggesting that infection history boosts vaccine responses.

Persistent and durable immunological memory forms the basis of any successful vaccination protocol. Generation of pre-existing memory B cell and T cell pools is thus the key for maintaining protective immunity to seasonal, pandemic and avian influenza viruses. Long-lived antibody secreting cells (ASCs) are responsible for maintaining antibody levels in peripheral blood. Generated with CD4 T help after naïve B cell precursors encounter their cognate antigen, the linked processes of differentiation (including Ig class switching) and proliferation also give rise to memory B cells, which then can change rapidly to ASC status after subsequent influenza encounters. Given that influenza viruses evolve rapidly as a consequence of antibody-driven mutational change (antigenic drift), the current influenza vaccines need to be reformulated frequently and annual vaccination is recommended. Without that process of regular renewal, they provide little protection against \"drifted\" (particularly H3N2) variants and are mainly ineffective when a novel pandemic (2009 A/H1N1 \"swine\" flu) strain suddenly emerges. Such limitation of antibody-mediated protection might be circumvented, at least in part, by adding a novel vaccine component that promotes cross-reactive CD8 T cells specific for conserved viral peptides, presented by widely distributed HLA types. Such \"memory\" cytotoxic T lymphocytes (CTLs) can rapidly be recalled to CTL effector status. Here, we review how B cells and follicular T cells are elicited following influenza vaccination and how they survive into a long-term memory. We describe how CD8 CTL memory is established following influenza virus infection, and how a robust CTL recall response can lead to more rapid virus elimination by destroying virus-infected cells, and recovery. Exploiting long-term, cross-reactive CTL against the continuously evolving and unpredictable influenza viruses provides a possible mechanism for preventing a disastrous pandemic comparable to the 1918-1919 H1N1 \"Spanish flu,\" which killed more than 50 million people worldwide.

Antiseizure medications (ASMs) are frequently implicated in T cell-mediated drug hypersensitivity reactions and cause skin tropic pathologies that range in severity from mild rashes to life-threatening systemic syndromes. During the acute stages of the more severe manifestations of these reactions, drug responsive proinflammatory CD8 + T cells display classical features of Th1 cytokine production ( e.g. IFNγ) and cytolysis ( e.g. granzyme B, perforin). These T cells may be found locally at the site of pathology ( e.g. blister cells/fluid), as well as systemically ( e.g. blood, organs). What is less understood are the long-lived immunological effects of the memory T cell pool following T cell-mediated drug hypersensitivity reactions. In this study, we examine the ASM carbamazepine (CBZ) and the CBZ-reactive memory T cell pool in patients who have a history of either Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) from 3-to-20 years following their initial adverse reaction. We show that in vitro drug restimulation of CBZ-reactive CD8 + T cells results in a proinflammatory profile and produces a mainly focused, yet private, T cell receptor (TCR) usage amongst human leukocyte antigen (HLA)-B*15:02-positive SJS or TEN patients. Additionally, we show that expression of these CBZ-reactive TCRs in a reporter cell line, lacking endogenous αβTCR, recapitulates the features of TCR activation reported for ASM-treated T cell lines/clones, providing a useful tool for further functional validations. Finally, we conduct a comprehensive evaluation of the HLA-B*15:02 immunopeptidome following ASM (or a metabolite) treatment of a HLA-B*15:02-positive B-lymphoblastoid cell line (C1R.B*15:02) and minor perturbation of the peptide repertoire. Collectively, this study shows that the CBZ-reactive T cells characterized require both the drug and HLA-B*15:02 for activation and that reactivation of memory T cells from blood results in a focused private TCR profile in patients with resolved disease.

Multiple myeloma (MM) is an uncontrolled plasma cell proliferation in the bone marrow, leading to immune dysregulation with impaired humoral immune responses. Conversely, cellular-based responses play a vital role in MM patients. However, the extent and duration of cellular-induced protection remain unclear to date. Here, immunomodulatory drugs (IMiDs) like Lenalidomide (Lena) become interesting, as they may have stimulatory effects on T-cell functioning. In this study we investigated immune responses elicited by COVID-19 vaccine or infection comparing 43 healthy volunteers (avg. 35y, 72.1% female, 81.4% previously COVID-19 infected), with 41 MM patients under Lena maintenance therapy (avg. 63.8y, 51.2% female, 61% previously COVID-19 infected). Humoral responses to SARS-CoV-2 spike (S), spike-RBD, and nucleocapsid (N) were measured via ELISA in subjects' plasma. Freshly isolated PBMCs, incubated with SARS-CoV-2 peptides (N, S), activation induced marker (AIM) assays and flow cytometry, allowed us to assess cellular responses (CD8 T, T : CD4 T (follicular) helper). Whereas healthy controls showed significant better humoral responses (N IgA p<0.001), T cell responses were robust in the MM group (higher S-act. T , p<0.001). Stratified by COVID-19 status, the MM group showed higher N-act. T (p=0.03). These results were unchanged comparing a Lena intake with Lena break around vaccination. Taken together, MM patients under Lena therapy exhibit weakened antibody production but present a robust T cell response following SARS-COV-2 infection or vaccination. Our results highlight the importance of vaccination in this subgroup and moreover, argue against a Lena intake break around the time of vaccination.

CD8 + T cells are a pivotal part of the immune response to viruses, playing a key role in disease outcome and providing long-lasting immunity to conserved pathogen epitopes. Understanding CD8 + T cell immunity in humans is complex due to CD8 + T cell restriction by highly polymorphic Human Leukocyte Antigen (HLA) proteins, requiring T cell epitopes to be defined for different HLA allotypes across different ethnicities. Here we evaluate strategies that have been developed to facilitate epitope identification and study immunogenic T cell responses. We describe an immunopeptidomics approach to sequence HLA-bound peptides presented on virus-infected cells by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Using antigen presenting cell lines that stably express the HLA alleles characteristic of Indigenous Australians, this approach has been successfully used to comprehensively identify influenza-specific CD8 + T cell epitopes restricted by HLA allotypes predominant in Indigenous Australians, including HLA-A*24:02 and HLA-A*11:01. This is an essential step in ensuring high vaccine coverage and efficacy in Indigenous populations globally, known to be at high risk from influenza disease and other respiratory infections.

Despite annual vaccination, influenza B viruses (IBV) cause significant disease with substantial health and socio-economic impacts. Novel vaccination strategies inducing broadly protective and long-lasting immunity across IBV lineages are needed. However, as immune responses toward IBV are largely understudied, host–virus interactions and protective immune mechanisms need to be defined to rationally design such vaccines. Here, we summarize recent advances in our understanding of immunological mechanisms underpinning protection from IBV. We discuss how innate antiviral host factors inhibit IBV replication and the ways by which IBV escapes such restriction. We review the specificity of broadly cross-reactive antibodies and universal T cells, and the mechanisms by which they mediate protection. We highlight important knowledge gaps needing to be addressed to design improved IBV vaccines.

An improved understanding of human T cell-mediated immunity in COVID-19 is important for optimizing therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8⁺ T cell memory to peptides presented by common HLA types like HLA-A2, which enhances recovery and diminishes clinical severity upon reinfection. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the clonal expansion of SARS-CoV-2−specific CD8⁺ and CD4⁺ T cells in vitro, with CD4⁺ T cells being robust. We identified two HLA-A*02:01-restricted SARS-CoV-2-specfic CD8⁺ T cell epitopes, A2/S269–277 and A2/Orf1ab3183–3191. Using peptide−HLA tetramer enrichment, direct ex vivo assessment of A2/S269⁺CD8⁺ and A2/Orf1ab3183⁺CD8⁺ populations indicated that A2/S269⁺CD8⁺ T cellswere detected at comparable frequencies (∼1.3 × 10−5) in acute and convalescent HLA-A*02:01⁺ patients. These frequencies were higher than those found in uninfected HLA-A*02:01⁺ donors (∼2.5 × 10−6), but low when compared to frequencies for influenza-specific (A2/M158) and Epstein–Barr virus (EBV)-specific (A2/BMLF1280) (∼1.38 × 10−4) populations. Phenotyping A2/S269⁺CD8⁺ T cells from COVID-19 convalescents ex vivo showed that A2/S269⁺CD8⁺ T cells were predominantly negative for CD38, HLA-DR, PD-1, and CD71 activation markers, although the majority of total CD8⁺ T cells expressed granzymes and/or perforin. Furthermore, the bias toward naïve, stem cell memory and central memory A2/S269⁺CD8⁺ T cells rather than effector memory populations suggests that SARS-CoV-2 infection may be compromising CD8⁺ T cell activation. Priming with appropriate vaccines may thus be beneficial for optimizing CD8⁺ T cell immunity in COVID-19.

The concept of chimeric antigen receptor (CAR) T cell therapy emerged from cancer immunotherapy and has been rapidly adapted and developed for the treatment of autoimmune, especially B-cell-driven, diseases since the first publication of an article featuring a patient with systemic lupus erythematosus in 2021. Phase II studies are about to start, but up to now, only case reports and small series have been published. In contrast to hemato-oncological diseases, where an aggressive response to malignant cells and long-lasting persistence of CAR T cells has been aimed at and observed in many patients, this is not the case with autoimmune diseases but might not be necessary to control disease. Future studies will focus on the optimal target but also on the optimal level of immunogenicity. The latter can be influenced by numerous modulations that affect not only cytokine release but also regulation. In addition, there are potential applications in regulatory cells such as CAR regulatory T cells (Treg). The question of toxicity reduction must also be addressed, as long-term complications such as the potential development of malignant diseases, infections, or cytopenia must be considered even more critically in the area of autoimmune diseases than is the case for patients with oncologic diseases. Alternative antibody-based therapies using the same target (e.g., CD3/CD19 bispecific targeting antibodies) have not been used in these patients and might also be considered in the future. In conclusion, CAR T cell therapy represents a promising therapeutic approach for autoimmune diseases, offering a targeted strategy to modulate immune responses and restore immune tolerance.