No abstract

The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants.

Iron is critical for life but toxic in excess because of iron-catalysed formation of pro-oxidants that cause tissue damage in a range of disorders. The Nrf2 transcription factor orchestrates cell-intrinsic protective antioxidant responses, and the peptide hormone hepcidin maintains systemic iron homeostasis, but is pathophysiologically decreased in haemochromatosis and beta-thalassaemia. Here, we show that Nrf2 is activated by iron-induced, mitochondria-derived pro-oxidants and drives Bmp6 expression in liver sinusoid endothelial cells, which in turn increases hepcidin synthesis by neighbouring hepatocytes. In Nrf2 knockout mice, the Bmp6-hepcidin response to oral and parenteral iron is impaired and iron accumulation and hepatic damage are increased. Pharmacological activation of Nrf2 stimulates the Bmp6-hepcidin axis, improving iron homeostasis in haemochromatosis and counteracting the inhibition of Bmp6 by erythroferrone in beta-thalassaemia. We propose that Nrf2 links cellular sensing of excess toxic iron to control of systemic iron homeostasis and antioxidant responses, and may be a therapeutic target for iron-associated disorders.

Germinal centers (GC) are microanatomical structures critical for the development of high-affinity antibodies and B-cell memory. They are organised into two zones, light and dark, with coordinated roles, controlled by local signalling. The innate Lectin-like transcript 1 (LLT1) is known to be expressed on B-cells, but its functional role in the GC reaction has not been explored. Here we report high expression of LLT1 on GC-associated B-cells, early plasmablasts and GC-derived lymphomas. LLT1 expression was readily induced via BCR, CD40 and CpG stimulation on B-cells. Unexpectedly, we found high expression of the LLT1 ligand, CD161, on Follicular dendritic cells (FDCs). Triggering of LLT1 supported B-cell activation, CD83 upregulation and CXCR4 downregulation. Overall, these data suggest that LLT1-CD161 interactions play a novel and important role in B-cell maturation within the GC in humans.