Biology subjects

Toellner, K.-M.

Publications and source records attributed to Toellner, K.-M..

6 recordsLinked to original sources

bioRxiv2025

Towards active vaccination against tumour endothelial marker Robo4

Targeting tumour antigens is a major challenge in cancer-immunotherapy. We use active vaccination to induce antibodies targeting self-antigen Robo4, which is selectively expressed on tumour vascular endothelium, supporting vascular development. Our previous work showed that a conjugate of Robo4 with a foreign carrier protein can induce autoantibodies specific to Robo4, which inhibited angiogenesis and tumour growth. The current project aims to translate the vaccine protocol to exploit a carrier protein used in routine human vaccination schedules. The well-characterised, non-toxic fragment C of tetanus toxin (TTc) was selected as the carrier protein. Here we show that priming with the carrier TTc followed by boost with Robo4-TTc (R4-TTc) efficiently induces strong antibody responses to Robo4 and inhibits tumour growth in LLC1 and 4T1 tumour models. The growth inhibition was correlated with anti-Robo4 IgG1 titres. Furthermore, we observed decreased vessel formation and increased immune cell infiltration in tumours from R4-TTc vaccinated mice in the absence of detectable adverse effects on health. The data indicate that this vaccination strategy remodels tumour vessels and probably promotes immunogenic pathway activation, therefore repressing tumour growth. One Sentence SummaryA conjugate vaccine inducing antibody responses to tumour endothelial markers Robo4 can inhibit tumour growth.

immunology↗

bioRxiv2023

Regulation of BCR-mediated Ca2+ mobilization by MIZ1-TIMBIM4 safeguards IgG1+ GC B cell positive selection

The transition from IgM to affinity-matured IgG antibodies is vital for effective humoral immunity. This is facilitated by germinal centers (GCs) through affinity maturation and preferential accumulation of IgG+ B cells over IgM+ B cells. However, it is not known whether the positive selection of the different immunoglobulin isotypes within GCs varies in its dependency on specific transcriptional mechanisms. Here, we identified IgG1+ GC B cell transcription factor dependency using CRISPR-Cas9 and conditional mouse genetics. We found that MIZ1 was specifically required for IgG1+ GC B cell survival during positive selection, whereas IgM+ GC B cells were largely independent. Mechanistically, MIZ1 induced TMBIM4, an ancestral anti-apoptotic protein that regulated inositol trisphosphate receptor mediated Ca2+ mobilization downstream of IgG1. The MIZ1-TMBIM4 axis prevented mitochondrial dysfunction-induced IgG1+ GC cell death caused by excessive Ca2+ accumulation. This study uncovers a unique immunoglobulin isotype-specific dependency, on a hitherto unidentified mechanism in GC positive selection.

immunology↗

bioRxiv2023

Vi polysaccharide and conjugated vaccines afford similar early, IgM or IgG-independent control of infection but boosting with conjugated Vi vaccines sustains the efficacy of immune responses

Vaccination with Vi capsular polysaccharide (Vi-PS) or protein-Vi typhoid conjugate vaccine (TCV) can protect adults against Salmonella Typhi infections. TCVs offer better protection than Vi-PS in infants and may offer better protection in adults. Potential reasons for why TCV may be superior in adults are not fully understood. Here, we immunized wild-type (WT) mice and mice deficient in IgG or IgM with Vi-PS or TCVs (Vi conjugated to tetanus toxoid or CRM197) for up to seven months, with and without subsequent challenge with Vi-expressing Salmonella Typhimurium. Unexpectedly, IgM or IgG alone were similarly able to reduce bacterial burdens in tissues, and this was observed in response to conjugated or unconjugated Vi vaccines and was independent of antibody being of high affinity. Only in the longer-term after immunization (>5 months) were differences observed in tissue bacterial burdens of mice immunized with Vi-PS or TCV. These differences related to the maintenance of antibody responses at higher levels in mice boosted with TCV, with the rate of fall in IgG titres induced to Vi-PS being greater than for TCV. Therefore, Vi-specific IgM or IgG are independently capable of protecting from infection and any superior protection from vaccination with TCV in adults may relate to responses being able to persist better rather than from differences in the antibody isotypes induced. These findings suggest that enhancing our understanding of how responses to vaccines are maintained may inform on how to maximize protection afforded by conjugate vaccines against encapsulated pathogens such as S. Typhi.

immunology↗

bioRxiv2021

Rhythmicity of Intestinal IgA Responses Confers Oscillatory Commensal Microbiota Mutualism

Mutualistic interactions with the commensal microbiota are enforced through a range of immune responses that confer metabolic benefits for the host and ensure tissue health and homeostasis. Immunoglobulin (Ig)A responses directly determine the composition of commensal species that colonize the intestinal tract but require significant metabolic resources to fuel antibody production by tissue-resident plasma cells. Here we demonstrate IgA responses are subject to diurnal regulation by dietary-derived metabolic cues and a cell-intrinsic circadian clock. Rhythmicity in IgA secretion conferred oscillatory patterns on the commensal microbial community and its associated metabolic activity, resulting in changes to metabolite availability over the course of the circadian day. Our findings suggest circadian networks comprising intestinal IgA, the diet and the microbiota align to ensure metabolic health. One-Sentence SummaryWe demonstrate diurnal rhythms in intestinal IgA act to cross-regulate oscillations in the abundance of commensal microbes to foster mutualism.

immunology↗

bioRxiv2020

Memory-like B cells emerging from germinal centres recycle through the subcapsular sinus

Infection or vaccination leads to the development of germinal centers (GCs) where B cells evolve high affinity antigen receptors, eventually producing antibody-forming plasma cells or memory B cells. We followed the migratory pathways of B cells emerging from germinal centers (BEM) and found that many migrated into the lymph node subcapsular sinus (SCS) guided by sphingosine-1-phosphate (S1P). From there, B cells may exit the lymph node to enter distant tissues. Some BEM cells interacted with and took up antigen from SCS macrophages, followed by CCL21-guided return towards the GC. Disruption of local CCL21 gradients inhibited the recycling of BEM cells and resulted in less efficient adaption to antigenic variation. Our findings suggest that the recycling of BEM cells, that transport antigen and that contain the genetic code for B cell receptor variants, may support affinity maturation to antigenic drift.

immunology↗

bioRxiv2020

Enhanced BCR signalling inflicts early plasmablast and germinal centre B cell death

It is still not clear how B-cell receptor (BCR) signalling intensity affects plasma cell and germinal centre (GC) B cell differentiation. We generated C{gamma}1Cre/+Ptpn6fl/fl mice where SHP-1, a negative regulator of BCR signalling, is deleted rapidly after B cell activation. Although immunisation with T-dependent antigens increased BCR signalling, it led to plasma cells reduction and increased apoptosis. Dependent on the antigen, the early GC B cell response was equally reduced and apoptosis increased. At the same time, a higher proportion of GC B cells expressed cMYC, indicating increased GC B cell - Tfh cell interactions. While GC B cell numbers returned to normal at later stages, affinity maturation was suppressed in the long term. This confirms that BCR signalling not only directs affinity dependent B cell selection but also, without adequate Tfh cell help, can inflict cell death, which may be important for the maintenance of B cell tolerance.

immunology↗