Expression of the co-stimulatory receptor 4-1BB is induced by T cell receptor recognition of antigen, while 4-1BB ligand is highly expressed on activated antigen presenting cells. 4-1BB signalling is particularly important for survival of activated and memory CD8+ T cells. We wished to test whether co-expression of antigen and 4-1BBL by dendritic cells (DC) would be an effective vaccine strategy. We therefore constructed lentiviral vectors (LV) co-expressing 4-1BBL and influenza nucleoprotein (NP). Following subcutaneous immunisation of mice, which targets DC, we found superior CD8+ T cell responses against NP and protection from influenza when 4-1BBL was expressed. However, functionally superior CD8+ T cell responses were obtained when two LV were co-injected, one expressing 4-1BBL, the other expressing NP. This surprising result suggested that 4-1BBL is more effective when expressed in trans, acting on adjacent DC. We therefore investigated the effect of LV expression of 4-1BBL in mouse DC cultures and observed induced maturation of bystander, untransduced cells. Maturation was blocked by anti-4-1BBL antibody, required cell-cell contact and did not require the cytoplasmic signalling domain of 4-1BBL. Greater maturation of untransduced cells could be explained by LV expression of 4-1BBL causing down-regulation of 4-1BB. These data suggest that co-expression of 4-1BBL and antigen by vaccine vectors that target DC may not be an optimal strategy. However, 4-1BBL LV immunisation activates significant numbers of bystander DC in the draining lymph nodes. Transactivation by 4-1BBL/4-1BB interaction following DC/DC contact may therefore play a role in the immune response to infection or vaccination.
The novel coronavirus (COVID-19) has emerged as a new pathogen responsible for an atypical viral pneumonia, with severe cases progressing to an acute respiratory distress syndrome. In our practice, we have observed patients admitted with COVID-19 pneumonia developing worsening hypoxaemic respiratory failure prompting the need for urgent endotracheal intubation. Here, we present a case of a patient admitted with severe COVID-19 pneumonia who required continuous positive airway pressure support following acute deterioration. However, with the patient requiring an increasing fraction of inspired oxygen (FiO2), a prompt CT pulmonary angiogram scan was performed to exclude an acute pulmonary embolism. Surprisingly, this revealed a pneumomediastinum. Following a brief admission to the intensive care unit, the patient made a full recovery and was discharged 18 days post admission.
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