Biology subjects

Lautenbach, M. J.

Publications and source records attributed to Lautenbach, M. J..

5 recordsLinked to original sources

bioRxiv2025

CD11c+ Memory B Cell Differentiation Across Blood and Tonsil Follows Origin-Specific Routes Revealed by CD24/CD27 Profiling

Atypical B cells (ABCs) are observed across infections, yet their ontogeny and differentiation remain unclear. Using high-dimensional flow cytometry, single-cell transcriptomics, V(D)J sequencing, and functional assays in human malaria and healthy donors, we identified markers of cellular origin while tracking ABC differentiation. Early ABCs express CD11c and arise predominantly from memory B cells. Two intermediate states originate from germinal center-derived and marginal zone-like B cells. Pseudotime and lineage analyses reveal trajectories marked by progressive CD24 and CD27 loss, recapitulated in vitro, defining bona fide differentiation programs. Differentiation culminates in late ABCs lacking CD24, CD27, and CD21, with high CD11c, T-bet, and NKG7, partly overlapping with double-negative 2 cells. Early- and intermediate stages show greater plasma-cell differentiation potential and cytokine production capacity, whereas later stages acquire antigen-presentation transcriptomic signatures and microbial-particle association, defining stage-dependent functions that reconcile conflicting ABC roles. Comparable ABC populations occur in healthy blood and tonsils, with tissue-associated class switching and CD86 expression consistent with recent T-cell interaction. This framework consolidates ABC definitions onto a single differentiation axis and clarifies cellular origins. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/676235v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@140364corg.highwire.dtl.DTLVardef@accbb5org.highwire.dtl.DTLVardef@720dc3org.highwire.dtl.DTLVardef@1e591f3_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Previous malaria exposure attenuates monocyte-driven inflammation and shapes B cell immunity

Clinical immunity to malaria develops after repeated malaria episodes. In this process, the inflammatory response is modulated to respond less vigorously upon reinfection. Monocytes are a major source of pro-inflammatory mediators during blood-stage infection and are known to adapt to repeated pathogen exposure. Here, we investigated the impact of previous malaria exposure on monocytes during blood-stage malaria by comparing the response in previously exposed and primary infected individuals. We observed reduced levels of the proinflammatory chemokine CXCL10 in previously exposed individuals, linked to changes in CD16+ monocytes. Similarly, BAFF levels were lower in these individuals and associated with modulation of monocyte and dendritic cells. This affected the BAFF-BAFF-R axis, crucial for B cell responses, correlating with increasing parasite-specific antibody levels. Collectively, we present novel insights into how previous malaria exposure shapes monocyte responses during acute malaria and how these in turn correlate with modulation of the B cell compartment and humoral immune response.

immunology↗

bioRxiv2023

Regulation of B cell function and expression of CD11c, T-bet, and FcLR5 after infection and in response to different activation pathways

CD11c, FcRL5, or T-bet are commonly expressed by B cells expanding during inflammation, where they can make up >30% of mature B cells. However, the association between the proteins and differentiation and function in the host response remain largely unclear. We have assessed the co-expression of CD11c, T-bet and FcRL5 in an in vitro B cell culture system to determine how stimulation via the B cell receptor (BCR), toll-like receptor 9 (TLR9), and different cytokines influence CD11c, T-bet, and FcRL5 expression. We observed different expression dynamics for all markers, but a largely overlapping regulation of CD11c and FcRL5 in response to BCR and TLR9 activation, while T-bet was strongly dependent on IFN-{gamma} signalling. Investigating plasma cell differentiation and antigen-presenting cell (APC) functions, there was no association between marker expression and antibody secretion or T cell help. Rather the functions were associated with TLR9-signalling and B cell-derived IL-6 production, respectively. These results suggest that the expression of CD11c, FcRL5, and T-bet and plasma cell differentiation and improved APC functions occur in parallel and are regulated by similar activation signals, but that they are not interdependent.

immunology↗

bioRxiv2022

A genomic platform for surveillance and antigen discovery in Plasmodium spp. using long-read amplicon sequencing

Many vaccine candidate proteins are under strong selective pressure to diversify in terms of antigenicity. We present a sequencing and data analysis platform for epidemiological surveillance and discovery of indel-rich vaccine antigens by long-read circular consensus sequencing (CCS) in multiclonal pathogen isolates. Our platform uses 40 PCR primers to asymmetrically barcode and identify multiclonal infections in pools of up to 384 samples. We validated the method using 235 mock infections combining 10 synthetic variants of the indel-rich gene merozoite surface protein 2 of Plasmodium falciparum at different concentrations and infection complexities, as well as 95 isolates from P. falciparum-infected residents of Nyamisati, Tanzania. We also constructed a fully automated analysis pipeline that streamlines the processing and interpretation of epidemiological and antigenic diversity data from demultiplexed FASTQ files. This platform can be easily adapted to other polymorphic antigens of interest in Plasmodium and other human pathogens.

genomics↗

bioRxiv2021

Systems-level analysis of patients treated for acute P. falciparum malaria reveals a role for the humoral response and cytokine milieu in limiting γδ T cell expansion

The mechanism of acquisition and maintenance of natural immunity against Plasmodium falciparum malaria remains unclear. Although, clinical immunity develops over time with repeated malaria episodes, disease tolerance is more rapidly acquired compared to protective immunity. It remains unclear, how pre-existing immune responses impacts the mechanism responsible for disease tolerance. Here, we investigated a cohort of returning travelers treated for acute symptomatic P. falciparum malaria, either infected for the first time, or with a previous history of malaria. Through repeated sampling over one year in a malaria free setting, we were able to study the acute and longitudinal effects of the infection. We combined comprehensive immune cell and plasma protein profiling with integrated and data driven analysis, describing the immune landscape from acute disease to one year after infection. We identified a strong association between pro-inflammatory signatures and {gamma}{delta} T cell expansion. The association was significantly impacted by previous exposure to malaria, resulting in a dampened pro-inflammatory response, which translated to reduced V{delta}2+ {gamma}{delta} T cell expansion compared to primary infected individuals. The dampened inflammatory signal was associated with early expansion of Fc{gamma}RIII+ monocytes and parasite-specific antibodies of IgG1 and IgG3 isotypes. Our data suggest that the interplay of Fc{gamma}RIII+ monocytes and a cytophilic parasite-specific IgG during the early blood stage infection lead to lower parasitemia and a dampened pro-inflammatory response with reduced {gamma}{delta} T cell expansion. This enhanced control and reduced inflammation points to a potential mechanism on how tolerance is established following repeated malaria exposure. One Sentence SummaryA systems immunology analysis on natural malaria sheds light on disease tolerance mechanism associated with gamma delta T cell expansion

immunology↗