Biology subjects

Hoevelmeyer, N.

Publications and source records attributed to Hoevelmeyer, N..

8 recordsLinked to original sources

bioRxiv2026

OTUB1 controls marginal zone B-cell development by stabilizing RelA in a CD40-dependent manner

Ubiquitin-dependent regulation of NF-{kappa}B signaling is essential for B-cell homeostasis and fate decisions, yet the contribution of specific deubiquitinating enzymes remains incompletely defined. OTUB1, a lysine-48-specific deubiquitinase, has been broadly implicated in immune regulation, including control of NF-{kappa}B signaling and prevention of immune hyperactivation. Previous studies have demonstrated that B cell-specific deletion of OTUB1 leads to B cell hyperplasia, increased antibody production, and lupus-like autoimmunity, highlighting its importance in maintaining B cell tolerance and immune homeostasis. Using B cell-specific OTUB1-deficient mice, we show that loss of OTUB1 leads to a marked expansion of marginal zone (MZ) B cells and their precursor populations in the spleen, accompanied by an activated phenotype and enhanced proliferative responses, particularly upon CD40 stimulation. OTUB1 deficiency results in altered CD40-induced NF-{kappa}B signaling, characterized by enhanced I{kappa}B degradation and increased nuclear accumulation of p50-containing NF-{kappa}B complexes, despite reduced RelA stability. Mechanistically, we show that OTUB1 interacts with RelA, restricting its lysine-48-linked ubiquitination and proteasomal degradation, thereby stabilizing this key transcription factor. Collectively, these findings identify RelA as a novel OTUB1 target and uncover an additional layer of ubiquitin-dependent control of NF-{kappa}B signaling that governs splenic B-cell homeostasis and marginal zone B-cell development.

immunology↗

bioRxiv2026

A streamlined spectral cytometry method for FAD and NADH autofluorescence analysis in immunometabolic studies

Abstract/SummaryWe present a streamlined protocol that enables the characterization of the metabolic state of immune cell populations through their distinct NADH/FAD autofluorescence fingerprints using a FACSymphony A5 spectral cytometer. We demonstrate the utility of this approach by profiling the metabolic status of diverse splenic B-cell subsets and assessing metabolic changes associated with their activation state.

immunology↗

bioRxiv2026

Treg-derived IκBζ promotes their conversion into Th2-like effectors and drives type 2 inflammation via BATF

Regulatory T cells (Treg cells) maintain peripheral immune tolerance but display considerable plasticity in peripheral tissues. The molecular mechanisms governing their function and plasticity, particularly under inflammatory conditions, remain poorly defined. Here, we identify the NF-{kappa}B-associated transcriptional cofactor I{kappa}B{zeta} as a critical regulator of Treg cell plasticity and function. Enforced expression of I{kappa}B{zeta} in Treg cells triggered the excessive expansion of functionally impaired Treg cells, resulting in lymphadenopathy, splenomegaly, and systemic type 2 inflammation, most prominently in the lung. Mechanistically, I{kappa}B{zeta} modified BATF expression and function, thereby driving the cell-intrinsic production of Th2-associated cytokines by Treg cells. Conversely, Treg-specific deletion of I{kappa}B{zeta} constrained IL-33-mediated expansion of tissue Treg cells and surprisingly attenuated type 2 inflammation. Thus, I{kappa}B{zeta} functions as a molecular switch that reprograms regulatory T cells into Th2-like Treg cells, thereby perturbing peripheral immune tolerance. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/707402v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1ef0b17org.highwire.dtl.DTLVardef@c12eaaorg.highwire.dtl.DTLVardef@decc86org.highwire.dtl.DTLVardef@1458767_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Glycosylated GM-CSF expands B-1b cells and B-1b plasma cells and programs them for immunosuppression

The myeloid growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) exhibits paradoxical pro- and anti-inflammatory functions, but the factors determining these divergent outcomes remain unclear. Here, we report that this functional divergence is controlled by its glycosylation. Murine recombinant fully glycosylated GM-CSF (rgGM-CSF) specifically induces immunosuppressive cell types, whereas its recombinant non-glycosylated counterpart (rngGM-CSF) promotes effector immune cells. Using single-cell ATAC-sequencing and flow cytometry, we show that rgGM-CSF has a previously unrecognized ability to effectively expand IL-10+ LAG-3+ PD-L1+ B-1b plasma cells (PCs) with immunosuppressive properties and self reactive natural IgM secretion. Although rgGM-CSF also promotes the expansion of hematopoietic stem and progenitor cells (HSPCs) and monocytic myeloid-derived suppressor cells (M-MDSCs), adoptive transfer experiments demonstrate that the rgGM-CSF-induced B-1b PCs are responsible for an IL-10-dependent long-term protection in mice from experimental autoimmune-encephalomyelitis (EAE). Our data suggest that glycosylation enhances the systemic bioavailability and activity of GM-CSF and promotes the expansion of immunoregulatory cells rather than pro-inflammatory myeloid effector cells. Together, these results demonstrate that the dual activity of GM-CSF is controlled by its glycosylation, resulting in opposing immune functions. These findings support a re-evaluation of human rgGM-CSF (regramostim) as a potential therapeutic strategy for immunosuppression in transplantation and autoimmune diseases. Key pointsO_LIGlycosylated GM-CSF promotes B-1b cells and B-1b plasma cells expansion and establishes their long-term imprinting as IL-10+ LAG3+ PD-L1+ natural IgM secreting regulatory cells. C_LIO_LIAlbumin binding enhances the systemic activity of glycosylated GM-CSF in generating regulatory B-1b plasma cells. C_LIO_LIGlycosylated GM-CSF injections into mice expand M-MDSCs, but their suppressive iNOS production is only maintained short-term. C_LIO_LINon-glycosylated GM-CSF injections preferentially promote expansion of pro-inflammatory effector monocytes and neutrophils. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=179 HEIGHT=200 SRC="FIGDIR/small/703206v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1814c57org.highwire.dtl.DTLVardef@1bb0e95org.highwire.dtl.DTLVardef@1ba8011org.highwire.dtl.DTLVardef@12df69f_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Aging-Associated Microbiota Drives Treg Dysfunction via TNF Signaling

Aging is associated with a chronic, low-grade inflammatory state referred to as inflammaging, which contributes to impaired immune regulation and increased susceptibility to disease. While regulatory T (Treg) cells are key mediators of immune homeostasis, their role in the context of age-related inflammation remains poorly understood. Here we demonstrate that age-related changes in the microbiota promote impaired Treg cell function, resulting in the differentiation of inflammatory T cells. In agreement, we find that aged germ-free (GF) mice exhibited a more balanced immune profile, where the Treg cells are functional and pro-inflammatory mediators are reduced, suggesting that microbial exposure is essential for the establishment of inflammaging. Furthermore, we show that the use of old microbiota in young animals was sufficient to induce pro-inflammatory T cell responses and impaired mucosal Treg cell proliferation, while young microbiota restored Treg cell function in old animals. Mechanistically, we show that exposure to aged microbiota was associated with sustained TNF signaling, elevated oxidative stress, DNA damage, and increased expression of senescence markers such as {gamma}H2AX and p16 in Treg cells. These findings uncover a microbiota-TNF-dependent mechanism by which age-associated microbial dysbiosis drives Treg cell dysfunction and promotes immune aging, highlighting the therapeutic potential of microbiota-targeted strategies to restore immune homeostasis in the elderly.

immunology↗

bioRxiv2025

B cells maintain the homeostasis of splenic marginal zone antigen-presenting cells to promote the anti-viral CD8+ T cell response

Natural killer and CD8+ T cells are critical in the elimination of blood-borne viruses such as cytomegalovirus (CMV); however, the role of B cells in this process is less clear. Here, using the murine CMV (MCMV) infection model, we demonstrated that the B cell-deficient mice mounted a weaker primary virus-specific CD8+ T cell response than their wild-type counterparts, which was associated with increased viral transcription. Notably, we found that the contribution of B cells to the CD8+ T-cell-mediated anti-viral response was not associated with their ability to generate antibodies but with their ability to sustain Langerin+ type 1 conventional dendritic cells (cDC1s), a dendritic cells (DC) subset known for being involved in viral and bacterial clearance in the marginal zone of the spleen. Furthermore, we found that the presence of Langerin+ cDC1s is dependent on B cells expressing lymphotoxin (LT{beta}) to maintain CD169+ marginal metallophilic macrophages (MMMs). We further discovered, using ligand-receptor interaction analyses, that the communication between MMMs and Langerin+ cDC1s was mediated via VCAM1 - ITGA4/ITGB1 interaction. Thus, our data reveals that B cell regulate the development of MMMs in the spleen via LT{beta} expression and consequently sustain Langerin+ cDC1s homeostasis for effective initiation of an anti-viral CD8+ T cell response. Overall, our study offers a new perspective on how B cells maintain the homeostasis of antigen-presenting cells in the splenic marginal zone and thus indirectly affect the virus-specific CD8+ T cell response, which could potentially be extended to other infectious and autoimmune diseases as well as tumors.

immunology↗

bioRxiv2024

Prohibitin 2 is a Key Regulator of T Cell Proliferation, Differentiation, and Effector Functions in vivo

Prohibitin 2 (PHB2) is a highly conserved protein with essential roles in cell homeostasis and survival across different cell types. Previous studies have shown that the deletion of PHB2 results in an arrest in proliferation due to impaired mitochondrial function regulated by the dynamin-like GTPase OPA1. The function of PHB2 in immune cells remains unclear, however, some studies suggest that PHB2 plays a role in the cell membranes of B and T cells. In order to elucidate the role of PHB2 in immune cells, we generated PHB2-deficient T cells. Our findings reveal a pivotal role for PHB2 in the proliferation and differentiation of T cells. PHB2 deficiency inhibits T cell proliferation by inducing a cell cycle arrest at the G1 to S phase, thereby preventing the differentiation into effector T cells. Furthermore, in contrast to previous reports, T cells lacking PHB2 are more resistant to apoptosis. Metabolic analysis reveals that PHB2-deficient T cells fail to upregulate their glycolysis and oxidative phosphorylation upon activation, thus rendering them incapable to proliferate.

immunology↗

bioRxiv2023

Natural antibodies as "eat-me" signals for phagocytosis of necrotic cell debris at sites of tissue injury

Natural antibodies (NAbs) are circulating polyreactive immunoglobulins that bind endogenous and exogenous antigens. Here, we investigated the role of NAbs in driving the clearance of necrotic cell debris from injury sites. Using mouse models of liver injury, we observed that IgM and IgG NAbs opsonize necrotic debris in vivo by recognizing common self-molecules such as histones, actin, phosphoinositides and cardiolipin, but not phosphatidylserine. Importantly, mice lacking NAbs presented impaired recovery from liver injury, which was correlated to sustained presence of necrotic debris in the tissue, prolonged inflammation and reduced hepatocellular proliferation. Mechanistically, necrotic debris phagocytosis was dependent on NAbs in vitro and in vivo, and restitution with total immunoglobulins rescued the defective recovery from liver injury in immunodeficient mice. In summary, we showed that NAbs opsonize necrotic cell debris and act as "eat-me" signals for engulfment through Fc{gamma}Rs and CD11b, driving the recovery from tissue injury. HighlightsO_LINatural antibodies opsonize exposed self-antigens upon necrotic cell death. C_LIO_LIThe phagocytosis of necrotic cell debris requires natural antibodies, Fc{gamma}Rs and CD11b. C_LIO_LINatural antibodies drive cellular proliferation and tissue regeneration after liver injury. C_LIO_LITreatment with natural antibodies improves the recovery from liver injury in both immunodeficient and immunocompetent mice. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/533912v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1ac8a7org.highwire.dtl.DTLVardef@6b7714org.highwire.dtl.DTLVardef@156d7cdorg.highwire.dtl.DTLVardef@720fea_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗