Biology subjects

Netland, J.

Publications and source records attributed to Netland, J..

3 recordsLinked to original sources

bioRxiv2025

Anti-malaria RTS,S/AS01 vaccine generates a limited pool of memory B cells expressing specificities associated with protection

RTS,S/AS01, an adjuvanted subunit malaria vaccine, induces protective but short-lived anti- Plasmodium falciparum circumsporozoite protein (CSP) antibody titers. To better understand the lack of sustained protection post-vaccination, we analyzed CSP-specific B cells over time in malaria-naive individuals following immunization with RTS,S/AS01. Longitudinal analyses of the cellular responses revealed a shift in the specificity of CSP-specific B cells over time. Early post- vaccine responses were dominated by plamsablasts and class-switched memory B cells (MBCs) specific for the NANP-repeat region of CSP, epitopes associated with protective antibodies. However, the frequency of NANP-repeat-specific MBCs declines, while longer-term memory specific for the C-terminus of CSP persists. Despite being class-switched and affinity matured, C- term monoclonal antibodies derived from these MBCs failed to protect mice against a transgenic parasite challenge. Taken together, these findings suggest that RTS,S/AS01 induces a transient, protective NANP repeat-specific B cell response that is subsequently replaced by memory B cells with non-protective reactivities, potentially explaining its limited long-term efficacy and limited response to subsequent challenges or boosters.

immunology↗

bioRxiv2024

Monoclonal antibodies derived from B cells in subjects with cystic fibrosis reduce Pseudomonas aeruginosa burden in mice

Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations of antibodies identified using protein-immunized animal systems and required extensive engineering to optimize binding and/or reduce immunogenicity. Of note, PA infections are common in people with cystic fibrosis (pwCF), who are generally believed to mount normal adaptive immune responses. Here we utilized a tetramer reagent to detect and isolate PcrV-specific B cells in pwCF and, via single-cell sorting and paired-chain sequencing, identified the B cell receptor (BCR) variable region sequences that confer PcrV-specificity. We derived multiple high affinity anti-PcrV monoclonal antibodies (mAbs) from PcrV-specific B cells across 3 donors, including mAbs that exhibit potent anti-PA activity in a murine pneumonia model. This robust strategy for mAb discovery expands what is known about PA-specific B cells in pwCF and yields novel mAbs with potential for future clinical use.

immunology↗

bioRxiv2019

The Development of Optimally Responsive Plasmodium-specific CD73+CD80+ IgM+ Memory B cells Requires Intrinsic BCL6 expression butnot CD4+ Tfh cells

Humoral immunity depends upon long-lived, antibody-secreting plasma cells and memory B cells (MBCs). MBCs exhibit significant phenotypic and functional heterogeneity shaped by interactions with CD4+ T cells. It is currently unclear how specific CD4+ T cell interactions with B cells influence specific MBC subset generation. We used genetic ablation and antibody depletion to dissect key CD4+ T cell/B cell receptor-ligand pair interactions to define the critical signals that govern the development of specific MBC populations. While it has previously been suggested that germinal center (GC) experience is required for the development of CD73+CD80+ MBCs that rapidly form secondary plasmablasts, highly functional IgM+ MBCs differentiate in a BCL6 and CD4+ T cell-dependent, but GC-independent manner. BCL6 upregulation, in the presence or absence of a GC, can therefore serve as a predictor of long-lived, functional MBCs. One Sentence SummaryDifferential requirements of BCL6 and Tfh cells lead to the generation of functionally distinct memory B cell populations.

immunology↗