Biology subjects

Read, J. F.

Publications and source records attributed to Read, J. F..

4 recordsLinked to original sources

bioRxiv2026

Integrated single cell multiomic profiling and functional validation reveal distinct cellular routes to human plasma cell differentiation.

Upon activation, B cells undergo profound transcriptional, epigenetic, and metabolic reprogramming to form antibody secreting plasma cells bearing little resemblance to their progenitors. Here, we used single cell RNA and ATAC sequencing of primary and in vitro differentiating human B cells to identify multiple distinct plasma cell subsets and differentiation routes depending on the starting cell type. In primary tonsils, we observed two distinct plasma cell subsets distinguished by expression of CD44 variant 9 (CD44v9), CD38, CD31, and CD10. A transient and rare CD30+ intermediate was identified both in primary tonsils and in vitro. CD40, TLR9, and cytokine stimulation of naive and memory B cells yielded CD30+ cells, which then formed plasma cells that were exclusively CD44v9+. CD30+ intermediates were not generated from primary germinal center B cells as they differentiated into plasma cells, which mostly lacked expression of CD44v9. Analysis of single cell multiomic data and pharmacological inhibition experiments demonstrated that the CD30+ intermediate was promoted by the transcription factor MEF2C. BAFF and APRIL promoted further maturation of these cells to CD44v9+ plasma cells. These data suggest that human germinal center-independent and -dependent ontogenies are biased towards distinct differentiation routes and terminal plasma cells.

immunology↗

bioRxiv2025

Early, adjuvant-responsive epigenetic programs in B cells imprint subsequent plasma cell survival and the duration of humoral immunity

The duration of antibody production varies across different infections and vaccines. To define molecular programs that promote durable humoral immunity, we used mice deficient in ZBTB20, a transcription factor that is highly expressed by plasma cells and required to maintain antibody production in vivo. However, genetic deletion of Zbtb20 in long-lived plasma cells had no impact on the duration of antibody production. Instead, deletion of Zbtb20 in B cells only within the first week after immunization caused a subsequent failure to maintain plasma cells. Through single cell ATAC-sequencing, we observed elevated IRF8- and Ets-dependent epigenetic programs in ZBTB20-deficient B cells at 7 days post-immunization, whereas the corresponding transcriptional changes manifested ~1 week later. Switching from alum to an oil-in-water adjuvant suppressed Ets-dependent epigenetic programs and rescued ZBTB20-deficient antibody responses. Deletion of Irf8 also rescued ZBTB20-deficient antibody responses. Thus, B cell-intrinsic epigenetic programs imprint durable antibody production at a very early stage, prior to major transcriptional consequences and weeks before most long-lived plasma cells are formed.

immunology↗

bioRxiv2023

Mapping lung hematopoietic progenitors: Developmental kinetics and response to Influenza A viral infection

The bone marrow is a specialised niche responsible for the maintenance of hematopoietic stem and progenitor cells during homeostasis and inflammation. Recent studies however have extended this essential role to the extramedullary and extravascular lung microenvironment. Here, we provide further evidence for a reservoir of hematopoietic stem and progenitor cells within the lung from embryonic day 18.5 until adulthood. These lung progenitors display distinct microenvironment-specific developmental kinetics compared to their bone marrow counterparts, exemplified by a rapid shift from a common myeloid to megakaryocyte-erythrocyte progenitor dominated niche with increasing age. In adult mice, Influenza A viral infection results in a transient reduction in multipotent progenitors within the lungs, with a parallel increase in downstream granulocyte-macrophage progenitors and dendritic cell populations associated with acute viral infections. Our findings suggest lung hematopoietic progenitors play a role in re-establishing immunological homeostasis in the respiratory mucosa, which may have significant clinical implications for maintaining pulmonary health following inflammatory perturbation.

immunology↗

bioRxiv2023

Single cell transcriptomics reveals cell type specific features of developmentally regulated responses to lipopolysaccharide between birth and 5 years.

Human perinatal life is characterized by a period of extraordinary change during which newborns encounter abundant environmental stimuli and exposure to potential pathogens. To meet such challenges, the neonatal immune system is equipped with unique functional characteristics that adapt to changing conditions as development progresses across the early years of life, but the molecular characteristics of such adaptations remain poorly understood. The application of single cell genomics to birth cohorts provides an opportunity to investigate changes in gene expression programs elicited downstream of innate immune activation across early life at unprecedented resolution. In this study, we performed single cell RNA-sequencing of mononuclear cells collected from matched birth cord blood and 5-year peripheral blood samples following stimulation (18hrs) with two well-characterized innate stimuli; lipopolysaccharide (LPS) and Polyinosinic:polycytidylic acid (Poly(I:C)). We found that the transcriptional response to LPS was constrained at birth and predominantly partitioned into classical proinflammatory gene upregulation primarily by monocytes and IFN-signaling gene upregulation by lymphocytes. Moreover, these responses featured substantial cell-to-cell communication which appeared markedly strengthened between birth and 5 years. In contrast, stimulation with Poly(I:C) induced a robust IFN-signalling response across all cell types identified at birth and 5 years. Analysis of gene regulatory networks revealed IRF1 and STAT1 were key drivers of the LPS-induced IFN-signaling response in lymphocytes with a potential developmental role for IRF7 regulation. Additionally, we observed distinct activation trajectory endpoints for monocytes derived from LPS-treated cord and 5-year blood, which was not apparent among Poly(I:C)-induced monocytes. Taken together, our findings provide new insight into the gene regulatory landscape of immune cell function between birth and 5 years and point to regulatory mechanisms relevant to future investigation of infection susceptibility in early life.

immunology↗