Zeb2 drives the formation of CD11c atypical B cells to sustain germinal centers that control persistent infection.

CD11c atypical B cells (ABCs) are an alternative memory B cell lineage associated with immunization, infection, and autoimmunity. However, the factors that drive the transcriptional program of ABCs have not been identified, and the function of this population remains incompletely understood. Here, we identified candidate transcription factors associated with the ABC population based on a human tonsillar B cell single-cell dataset.

Response to COVID-19 vaccination in patients on cancer therapy: Analysis in a SARS-CoV-2-naïve population.

Background: Cancer patients have increased morbidity and mortality from COVID-19, but may respond poorly to vaccination. The Evaluation of COVID-19 Vaccination Efficacy and Rare Events in Solid Tumors (EVEREST) study, comparing seropositivity between cancer patients and healthy controls in a low SARS-CoV-2 community-transmission setting, allows determination of vaccine response with minimal interference from infection.

Methods: Solid tumor patients from The Canberra Hospital, Canberra, Australia, and healthy controls who received COVID-19 vaccination between March 2021 and January 2022 were included.

Heterogeneity in killing efficacy of individual effector CD8 T cells against Plasmodium liver stages.

Vaccination strategies in mice inducing high numbers of memory CD8 T cells specific to a single epitope are able to provide sterilizing protection against infection with Plasmodium sporozoites. We have recently found that Plasmodium-specific CD8 T cells cluster around sporozoite-infected hepatocytes but whether such clusters are important in elimination of the parasite remains incompletely understood. Here, we used our previously generated data in which we employed intravital microscopy to longitudinally image 32 green fluorescent protein (GFP)-expressing parasites in livers of mice that had received activated Plasmodium-specific CD8 T cells after sporozoite infection.

mRNA vaccine against malaria tailored for liver-resident memory T cells.

Malaria is caused by Plasmodium species transmitted by Anopheles mosquitoes. Following a mosquito bite, Plasmodium sporozoites migrate from skin to liver, where extensive replication occurs, emerging later as merozoites that can infect red blood cells and cause symptoms of disease. As liver tissue-resident memory T cells (Trm cells) have recently been shown to control liver-stage infections, we embarked on a messenger RNA (mRNA)-based vaccine strategy to induce liver Trm cells to prevent malaria.

A New Method Based on the von Mises-Fisher Distribution Shows that a Minority of Liver-Localized CD8 T Cells Display Hard-To-Detect Attraction to -Infected Hepatocytes.

Malaria is a disease caused by parasites, resulting in over 200 million infections and 400,000 deaths every year. A critical step of malaria infection is when sporozoites, injected by mosquitoes, travel to the liver and form liver stages. Malaria vaccine candidates which induce large numbers of malaria-specific CD8 T cells in mice are able to eliminate all liver stages, preventing fulminant malaria.

Housebreaking Plasmodium parasites leave their fingerprints at the door.

Protective antibodies against Plasmodium falciparum merozoite antigens, including EBA-175, can inhibit erythrocyte invasion. New data from Musasia et al. indicate that these antibodies can also trigger antibody-dependent phagocytosis of ring-infected and uninfected erythrocytes and that this correlates with protection from malaria.

The development and function of CD11c atypical B cells - insights from single cell analysis.

CD11c T-bet atypical B cells (ABCs) have been identified in the context of vaccination, acute and chronic infections and autoimmune disease. However, the origins and functions of ABCs remain elusive. A major obstacle in the study of ABCs, and human MBCs more generally, has been the use of different phenotypic markers in different contexts to identify what appear to be phenotypically similar cells.

Extrafollicular Plasmablasts Present in the Acute Phase of Infections Express High Levels of PD-L1 and Are Able to Limit T Cell Response.

During infections with protozoan parasites or some viruses, T cell immunosuppression is generated simultaneously with a high B cell activation. It has been described that, as well as producing antibodies, plasmablasts, the differentiation product of activated B cells, can condition the development of protective immunity in infections. Here, we show that, in infection, all the plasmablasts detected during the acute phase of the infection had higher surface expression of PD-L1 than other mononuclear cells.

Interactions with Asialo-Glycoprotein Receptors and Platelets Are Dispensable for CD8 T Cell Localization in the Murine Liver.

Liver-resident CD8 T cells can play critical roles in the control of pathogens, including and hepatitis B virus. Paradoxically, it has also been proposed that the liver may act as the main place for the elimination of CD8 T cells at the resolution of immune responses. We hypothesized that different adhesion processes may drive residence versus elimination of T cells in the liver.

Splenic Dendritic Cells and Macrophages Drive B Cells to Adopt a Plasmablast Cell Fate.

Upon encountering cognate antigen, B cells can differentiate into short-lived plasmablasts, early memory B cells or germinal center B cells. The factors that determine this fate decision are unclear. Past studies have addressed the role of B cell receptor affinity in this process, but the interplay with other cellular compartments for fate determination is less well understood.

Liver Environment-Imposed Constraints Diversify Movement Strategies of Liver-Localized CD8 T Cells.

Pathogen-specific CD8 T cells face the problem of finding rare cells that present their cognate Ag either in the lymph node or in infected tissue. Although quantitative details of T cell movement strategies in some tissues such as lymph nodes or skin have been relatively well characterized, we still lack quantitative understanding of T cell movement in many other important tissues, such as the spleen, lung, liver, and gut. We developed a protocol to generate stable numbers of liver-located CD8 T cells, used intravital microscopy to record movement patterns of CD8 T cells in livers of live mice, and analyzed these and previously published data using well-established statistical and computational methods.

Avid binding by B cells to the Plasmodium circumsporozoite protein repeat suppresses responses to protective subdominant epitopes.

Antibodies targeting the NANP/NVDP repeat domain of the Plasmodium falciparum circumsporozoite protein (CSP) can protect against malaria. However, it has also been suggested that the CSP is a decoy that prevents the immune system from mounting responses against other domains of CSP. Here, we show that, following parasite immunization, B cell responses to the CSP are immunodominant over responses to other CSP domains despite the presence of similar numbers of naive B cells able to bind these regions.

A Point Mutation in IKAROS ZF1 Causes a B Cell Deficiency in Mice.

IKZF1 (IKAROS) is essential for normal lymphopoiesis in both humans and mice. Previous mouse models have demonstrated the dual role for IKZF1 in both B and T cell development and have indicated differential requirements of each zinc finger. Furthermore, mutations in are known to cause common variable immunodeficiency in patients characterized by a loss of B cells and reduced Ab production.

Atypical B cells are part of an alternative lineage of B cells that participates in responses to vaccination and infection in humans.

The diversity of circulating human B cells is unknown. We use single-cell RNA sequencing (RNA-seq) to examine the diversity of both antigen-specific and total B cells in healthy subjects and malaria-exposed individuals. This reveals two B cell lineages: a classical lineage of activated and resting memory B cells and an alternative lineage, which includes previously described atypical B cells.

The challenges of a circumsporozoite protein-based malaria vaccine.

Introduction: A safe and effective vaccine will likely be necessary for the control or eradication of malaria which kills 400,000 annually. Our most advanced vaccine candidate to date is RTS,S which is based on the circumsporozoite protein (PfCSP) of the malaria parasite. However, protection by RTS,S is incomplete and short-lived.

Development of Plasmodium-specific liver-resident memory CD8 T cells after heat-killed sporozoite immunization in mice.

Malaria remains a major cause of mortality in the world and an efficient vaccine is the best chance of reducing the disease burden. Vaccination strategies for the liver stage of disease that utilise injection of live radiation-attenuated sporozoites (RAS) confer sterile immunity, which is mediated by CD8 memory T cells, with liver-resident memory T cells (T ) being particularly important. We have previously described a TCR transgenic mouse, termed PbT-I, where all CD8 T cells recognize a specific peptide from Plasmodium.

Prevalence of asymptomatic SARS-CoV-2 infection in elective surgical patients in Australia: a prospective surveillance study.

Background: The study aimed to estimate the prevalence of active or previous SARS-CoV-2 infection in asymptomatic adults admitted for elective surgery in Australian hospitals. This surveillance activity was established as part of the National Pandemic Health Intelligence Plan.

Methods: Participants (n = 3037) were recruited from 11 public and private hospitals in four states (NSW, Vic, SA and WA) between 2 June and 17 July 2020, with an overall 66% participation rate.

A Potent Anti-Malarial Human Monoclonal Antibody Targets Circumsporozoite Protein Minor Repeats and Neutralizes Sporozoites in the Liver.

Discovering potent human monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on sporozoites (SPZ) and elucidating their mechanisms of neutralization will facilitate translation for passive prophylaxis and aid next-generation vaccine development. Here, we isolated a neutralizing human mAb, L9 that preferentially bound NVDP minor repeats of PfCSP with high affinity while cross-reacting with NANP major repeats. L9 was more potent than six published neutralizing human PfCSP mAbs at mediating protection against mosquito bite challenge in mice.

Antibody Feedback Limits the Expansion of B Cell Responses to Malaria Vaccination but Drives Diversification of the Humoral Response.

Generating sufficient antibody to block infection is a key challenge for vaccines against malaria. Here, we show that antibody titers to a key target, the repeat region of the Plasmodium falciparum circumsporozoite protein (PfCSP), plateaued after two immunizations in a clinical trial of the radiation-attenuated sporozoite vaccine. To understand the mechanisms limiting vaccine responsiveness, we developed immunoglobulin (Ig)-knockin mice with elevated numbers of PfCSP-binding B cells.