Biology subjects

Forsell, M. N.

Publications and source records attributed to Forsell, M. N..

5 recordsLinked to original sources

bioRxiv2025

A conserved transcriptional backbone and rewiring of gene-regulatory networks in activated human CD4⁺ T cells

CD4+ T cells are components of the adaptive immune system with a plethora of subtype-specific functions. In order to further dissect the activation and differentiation regulatory program(s) of individual CD4+ T cell subsets, we performed an in vitro activation and differentiation of human primary naive CD4+ T cells towards Th1, Th2, Th17 and Treg subtypes followed by the single-cell RNA-seq and ATAC-seq (multiome) analysis. Resulting multiome data were used for constructing the subtype-specific gene regulatory networks, which were next assessed for their differences/similarities among the subtypes. Surprisingly, a conserved set of 8 "backbone" transcription factors (TFs) was identified as highly central in all subtypes, however, with unique differentiation-driven rewiring tendency. Subtype-specific "driver" TFs were identified in the case of Th1-Th1_17-Th17 lineage (EOMES, HLF), naive Tregs (ESR1, DACH1), and memory Tregs (SOX13). Finally, we applied community detection algorithms to identify potential non-obvious groups of genes that regulate diverse molecular functions within the differentiated subtypes, linked to the backbone TFs. Our atlas aims at providing a high resolution understanding of the gene regulatory networks and their rewiring in human primary CD4+ T cells, upon activation and differentiation.

immunology↗

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↗

bioRxiv2024

The CD4 T cell epigenetic JUNB+ state is associated with proliferation and exhaustion

Adoptive cell therapy (ACT) requires the in vitro expansion of T cells, a process where currently several variables are poorly controlled. As the state and quality of the cells affects the treatment outcome, the lack of insight is problematic. To get a better understanding of the production process and its degrees of freedom, we have generated a multiome CD4 T cell single-cell atlas. We find in particular a JUNB+ epigenetic state, orthogonal to traditional CD4 T cell subtype categorization. This new state is present but overlooked in previous transcriptomic CD4 T cell atlases. We characterize it to be highly proliferative, having condensed and actively remodeled chromatin, and correlating with exhaustion. JUNB+ subsets are also linked to memory formation, as well as circadian rhythm, connecting several important processes into one state. To dissect JUNB regulation, we also derived a gene regulatory network (GRN) and developed a new explainable machine learning package, Nando. We propose potential upstream drivers of JUNB, verified by other atlases and orthogonal data. We expect our results to be relevant for optimizing in vitro ACT conditions as well as modulation of gene expression through novel gene editing.

immunology↗

bioRxiv2022

Recall of pre-existing cross-reactive B cell memory following Omicron breakthrough infection

Understanding immune responses following SARS-CoV-2 breakthrough infection will facilitate the development of next-generation vaccines. Here, we profiled spike (S)-specific B cell responses following Omicron/BA.1 infection in mRNA-vaccinated donors. The acute antibody response was characterized by high levels of somatic hypermutation (SHM) and a bias toward recognition of ancestral SARS-CoV-2 strains, suggesting the early activation of vaccine-induced memory B cells (MBCs). BA.1 breakthrough infection induced a shift in B cell immunodominance hierarchy from the S2 subunit toward the receptor binding domain (RBD). A large proportion of RBD-directed neutralizing antibodies isolated from BA.1 breakthrough infection donors displayed convergent sequence features and broadly recognized SARS-CoV-2 variants of concern (VOCs). Together, these findings provide fundamental insights into the role of pre-existing immunity in shaping the B cell response to heterologous SARS-CoV-2 variant exposure. One sentence summaryBA.1 breakthrough infection activates pre-existing memory B cells with broad activity against SARS-CoV-2 variants.

immunology↗

bioRxiv2020

Regulation of Decay Accelerating Factor primes human germinal center B cells for phagocytosis

Germinal centers (GC) are sites for extensive B cell proliferation and homeostasis is maintained by programmed cell death. The complement regulatory protein Decay Accelerating Factor (DAF) blocks complement deposition host cells and therefore also phagocytosis of cells. Here, we show that B cells downregulate DAF upon BCR engagement and that T cell-dependent stimuli preferentially led to activation of DAFlo B cells. Consistent with this, a majority of light and dark zone GC B cells were DAFlo and susceptible to complement-dependent phagocytosis, as compared with DAFhi GC B cells. We could also show that the DAFhi GC B cell subset had increased expression of the plasma cell marker Blimp-1. DAF expression was also modulated during B cell hematopoiesis in the human bone marrow. Collectively, our results reveal a novel role of DAF to pre-prime activated human B cells for phagocytosis prior to apoptosis.

immunology↗