Doherty Institute - Research Publications
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ItemNo Preview AvailableCD4+ T cell calibration of antigen-presenting cells optimizes antiviral CD8+ T cell immunity(NATURE PORTFOLIO, 2023-06)Antiviral CD8+ T cell immunity depends on the integration of various contextual cues, but how antigen-presenting cells (APCs) consolidate these signals for decoding by T cells remains unclear. Here, we describe gradual interferon-α/interferon-β (IFNα/β)-induced transcriptional adaptations that endow APCs with the capacity to rapidly activate the transcriptional regulators p65, IRF1 and FOS after CD4+ T cell-mediated CD40 stimulation. While these responses operate through broadly used signaling components, they induce a unique set of co-stimulatory molecules and soluble mediators that cannot be elicited by IFNα/β or CD40 alone. These responses are critical for the acquisition of antiviral CD8+ T cell effector function, and their activity in APCs from individuals infected with severe acute respiratory syndrome coronavirus 2 correlates with milder disease. These observations uncover a sequential integration process whereby APCs rely on CD4+ T cells to select the innate circuits that guide antiviral CD8+ T cell responses.
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ItemDefective Severe Acute Respiratory Syndrome Coronavirus 2 Immune Responses in an Immunocompromised Individual With Prolonged Viral Replication(OXFORD UNIV PRESS INC, 2021-09)We describe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immune responses in a patient with lymphoma and recent programmed death 1 (PD-1) inhibitor therapy with late onset of severe coronavirus disease 2019 disease and prolonged SARS-CoV-2 replication, in comparison to age-matched and immunocompromised controls. High levels of HLA-DR+/CD38+ activation, interleukin 6, and interleukin 18 in the absence of B cells and PD-1 expression was observed. SARS-CoV-2-specific antibody responses were absent and SARS-CoV-2-specific T cells were minimally detected. This case highlights challenges in managing immunocompromised hosts who may fail to mount effective virus-specific immune responses.
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ItemIntegrated immune dynamics define correlates of COVID-19 severity and antibody responses(CELL PRESS, 2021-03-16)SARS-CoV-2 causes a spectrum of COVID-19 disease, the immunological basis of which remains ill defined. We analyzed 85 SARS-CoV-2-infected individuals at acute and/or convalescent time points, up to 102 days after symptom onset, quantifying 184 immunological parameters. Acute COVID-19 presented with high levels of IL-6, IL-18, and IL-10 and broad activation marked by the upregulation of CD38 on innate and adaptive lymphocytes and myeloid cells. Importantly, activated CXCR3+cTFH1 cells in acute COVID-19 significantly correlate with and predict antibody levels and their avidity at convalescence as well as acute neutralization activity. Strikingly, intensive care unit (ICU) patients with severe COVID-19 display higher levels of soluble IL-6, IL-6R, and IL-18, and hyperactivation of innate, adaptive, and myeloid compartments than patients with moderate disease. Our analyses provide a comprehensive map of longitudinal immunological responses in COVID-19 patients and integrate key cellular pathways of complex immune networks underpinning severe COVID-19, providing important insights into potential biomarkers and immunotherapies.
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ItemNo Preview AvailableBreadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19(NATURE PORTFOLIO, 2020-04)
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ItemRecalling the Future: Immunological Memory Toward Unpredictable Influenza Viruses(FRONTIERS MEDIA SA, 2019-07-02)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.
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ItemDistinguishing naive- from memory-derived human B cells during acute responses(WILEY, 2019)OBJECTIVES: A fundamental question in influenza research is whether antibody titre decline upon successive exposure to variant strains is consequent to recall of cross-reactive memory B cells that competitively inhibit naive B-cell responses. In connection, it is not clear whether naive and memory B cells remain phenotypically distinct acutely after activation such that they may be distinguished ex vivo. METHODS: Here, we first compared the capacity of anti-Ig and Toll-like-receptor (TLR) 7/8 and TLR9 agonists (R848 and CpG) to augment human B-cell differentiation induced by IL-21 and sCD40L. The conditions that induced optimal differentiation were then used to compare the post-activation phenotype of sort-purified naive and memory B-cell subsets by FACS and antibody-secreting cell (ASC) ELISPOT. RESULTS: Sort-purified naive and memory B cells underwent robust plasmablast and ASC formation when stimulated with R848, but not CpG, and co-cultured with monocytes. This coincided with increased IL-1β and IL-6 production when B cells were co-cultured with monocytes and stimulated with R848, but not CpG. Naive B cells underwent equivalent ASC generation, but exhibited less class-switch and modulation of CD27, CD38 and CD20 expression than memory B cells after stimulation with R848 and monocytes for 6 days. CONCLUSION: Stimulation with R848, IL-21 and sCD40L in the presence of monocytes induces robust differentiation and ASC generation from both naive and memory B-cells. However, naive and memory B cells retain key phenotypic differences after activation that may facilitate ex vivo discrimination and better characterisation of acute responses to variant antigens.