Biology subjects

Tarlinton, D. M.

Publications and source records attributed to Tarlinton, D. M..

5 recordsLinked to original sources

bioRxiv2026

The NKCC1 inhibitor bumetanide has no discernible effect on plasma cell survival, persistence or antibody secretion

Long-lived plasma cells (LLPC) sustain humoral immunity but also contribute to the persistence of pathogenic autoantibodies in autoimmune diseases. New therapies targeting LLPC are therefore desirable. Recent studies have shown increased expression of Slc12a2, encoding the Na+ -K+ -Cl- cotransporter (NKCC1), in LLPC. This study investigated whether NKCC1 activity was required for plasma cell survival, persistence or secretion of antibodies. Across in vitro and in vivo settings, mouse plasma cell survival was undiminished by treatment with the NKCC1 inhibitor bumetanide. Acute in vivo bumetanide treatment did not diminish plasma cell numbers, nor show any demonstrable impact on the survival of phenotypically mature I-A/I-EloSLAMF6lo plasma cells. With genetic plasma cell timestamping, even the survival of persistent LLPC was unaffected by bumetanide. Plasma cell secretory capacity, assessed by measuring IgM and IgG2b secretion in culture over three days, was also unaltered by bumetanide. Overall, these results show that pharmacological inhibition of NKCC1 is not sufficient to impair plasma cell survival, persistence or antibody secretion. Despite elevated Slc12a2 mRNA expression in LLPC, NKCC1 alone does not represent a critical plasma cell survival pathway, highlighting the resilience of plasma cells and the challenges associated with therapeutically targeting LLPC.

immunology↗

bioRxiv2025

Antibody responses against bacterial glycans affinity mature and diversify in germinal centers.

Anti-carbohydrate antibodies (Abs) play crucial roles in pathogen control, but their generation remains poorly understood. By studying responses to Streptococcus pyogenes in humans, we reveal that the glycan-targeted response shifts from IgM towards IgG and IgA memory with age and antigen exposure across blood, spleen, and tonsils. Both natural colonization and controlled human infection with S. pyogenes increased class-switched B cells, with evidence of within-clone switching. Glycan-specific B cells readily participated in germinal center (GC) responses and showed robust somatic hypermutation despite a molecular signature consistent with receiving reduced T cell help. We conclude that mucosal pathogen encounters elicit glycan responses that class-switch, evolve and diversify through the GC. These findings reveal how age and infection history can influence the quality, quantity, and isotype use of glycan-specific B cells, with implications for the design and schedule of glycan-containing vaccines.

immunology↗

bioRxiv2022

B cell receptor stimulation induces IgE plasma cell apoptosis

The proper regulation of IgE production safeguards against allergic disease, highlighting the importance of mechanisms that restrict IgE plasma cell (PC) survival. IgE PCs have unusually high surface B cell receptor (BCR) expression, yet the functional consequences of ligating this receptor are unknown. Here, we found that BCR ligation induced BCR signaling in IgE PCs followed by their elimination. In cell culture, exposure of IgE PCs to cognate antigen or anti-BCR antibodies induced apoptosis. IgE PC depletion correlated with the affinity, avidity, amount, and duration of antigen exposure and required the BCR signalosome components Syk, BLNK, and PLC{gamma}2. In mice with a PC-specific impairment of BCR signaling, the abundance of IgE PCs was selectively increased. Conversely, BCR ligation by injection of cognate antigen or anti-IgE depleted IgE PCs. These findings establish a mechanism for the elimination of IgE PCs through BCR ligation. This has important implications for allergen tolerance and immunotherapy as well as anti-IgE monoclonal antibody treatments.

immunology↗

bioRxiv2022

IL-21 lowers the B cell receptor affinity threshold for participation in a T cell dependent immune response.

The proliferation and differentiation of antigen-specific B cells, including the generation of germinal centers (GC), are prerequisites for long-lasting, high-affinity antibody-mediated immune protection. Affinity for antigen determines B cell recruitment, proliferation, differentiation and competitiveness in the response, largely through determining access to T cell help. However, how T cell derived signals contribute to these outcomes is incompletely understood. Here we report how the signature cytokine of follicular helper T cells, IL-21, acts as a key regulator of the initial B cell response. By activating AKT and S6, IL-21 accelerates cell cycle progression and the rate of cycle entry of B cells, increasing their contribution to the ensuing GC. This effect occurs over a wide range of initial B cell receptor affinities and the resultant increased proliferation can explain the IL-21-mediated promotion of plasma cell differentiation. Collectively, our data establish that IL-21 acts from the outset of a T cell dependent immune response to increase cell cycle progression and fuel cyclic re-entry of B cells thereby regulating the initial GC size and early plasma cell output. SummaryThe cytokine IL-21 is a regulator of B cell responses, increasing antibody quantity and quality. Here, we report that during germinal center initiation, IL-21 acts to increase the response magnitude by accelerating cell cycle speed and rate of entry.

immunology↗

bioRxiv2019

An Erg driven transcriptional program controls B-lymphopoiesis

Summary/AbstractB-cell development is initiated by the stepwise differentiation of hematopoietic stem cells into lineage committed progenitors, ultimately generating the mature B-cells that mediate protective immunity. This highly regulated process also generates clonal immunological diversity via recombination of immunoglobulin genes. While several transcription factors that control B-cell development and V(D)J recombination have been defined, how these processes are initiated and coordinated into a precise regulatory network remains poorly understood. Here, we show that the transcription factor ETS Related Gene (Erg) is essential for the earliest steps in B-cell differentiation. Erg initiates a transcriptional network involving the B-cell lineage defining genes, Ebf1 and Pax5, that directly promotes the expression of key genes involved in V(D)J recombination and formation of the B-cell receptor. Complementation of the Erg-deficiency with a productively rearranged immunoglobulin gene rescued B-cell development, demonstrating that Erg is an essential and exquisitely stage specific regulator of the gene regulatory network controlling B-lymphopoiesis.

immunology↗