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Spensberger, D.

Publications and source records attributed to Spensberger, D..

4 recordsLinked to original sources
bioRxiv2025

Selective alteration to CD4 T cell differentiation by heterozygous IRF4L116R protects against neuroinflammation

The decision of naive T cells to differentiate into a specific Th cell subset after antigen encounter is a critical pivot point of the immune response and, when out of balance, can lead to autoimmunity, allergy or immunodeficiency. Th subset differentiation is determined by the expression of transcription factors including IRF4. We here describe a point mutation (IRF4L116R) in the DNA-binding domain of IRF4 leading to a dysregulation of CD4-T cell subsets and their functions. This point mutation does not alter overall protein expression. In sharp contrast to IRF4-null mice, neither the CD4/CD8 ratio nor T cell activation and memory is altered in naive mice carrying the point mutation. However, IRF4L116R T cells are reduced in their capability to differentiate into Th1, Th17 and Treg cells in a dose-dependent manner, contrasting with the findings in IRF4KO T cells. Particularly striking is the loss of Th1-differentiation in T cells from homozygous Irf4L116R/L116R mice while T cells completely lacking IRF4 show no reduction in Th1 differentiation. Furthermore, despite maintained ability to generate Th17 cells, expression of the IRF4L116R variant protects mice against disease development in the Th17 cell-dependent EAE mouse model of neuroinflammation. This contrasts with IRF4 knock-out mice, where expression of one wild-type allele of IRF4 is sufficient for full disease development. Together our results show that the L116R point mutation in IRF4 can selectively alter the differentiation and function of some CD4 T cell subsets and suggest that the L116R mutation is not a classical loss- or gain-of-function variant.

immunology↗
bioRxiv2024

B cells targeting parasites capture spatially linked antigens to secure T cell help

Our understanding of T-cell-dependent humoral responses has been largely shaped by studies involving model antigens such as recombinant proteins and viruses 1,2. In these contexts, B cells internalize the entire antigen or pathogen, and present a range of antigens to helper CD4+ T cells to initiate the humoral response. However, this model does not account for large pathogens (such as parasites) that are too large to be taken up by individual B cells, and the mechanisms by which B cells acquire and present antigens from large complex pathogens to T cells remain poorly understood. Here we used Plasmodium, the causative parasite of malaria, as a model to investigate the requirements for T cell help for B cells targeting the Plasmodium surface circumsporozoite protein (CSP). Upon Plasmodium sporozoite (SPZ) immunization, CSP-specific B cells can form a synapse-like structure with SPZs and take up CSP and non-CSP surface antigens. As a result, CSP-specific B cells can receive help from CD4+ T cells specific to antigens that are located on the surface but not cytosol of the Plasmodium SPZ. Therefore, B cells can obtain help, not only from T cells with the same protein specificity, but also from T cells specific for spatially linked antigens. This flexibility in T cell help may enhance the initiation and maintenance of humoral immune responses to complex pathogens.

immunology↗
bioRxiv2023

PLEKHS1 drives PI3Ks and remodels pathway homeostasis in PTEN-null prostate

The PIP3/PI3K network is a central regulator of metabolism and is frequently activated in cancer, commonly by loss of the PIP3/PI(3,4)P2-phosphatase, PTEN. Despite huge investment, the drivers of the PI3K network in normal tissues and how they adapt to overactivation are unclear. We find that in healthy mouse prostate PI3K activity is driven by RTK/IRS signalling and constrained by pathway-feedback. In the absence of PTEN, the network is dramatically remodelled. A poorly understood, YXXM and PIP3/PI(3,4)P2-binding PH domain-containing, adaptor, PLEKHS1, became the dominant activator and was required to sustain PIP3, AKT-phosphorylation and growth in PTEN-null prostate. This was because PLEKHS1 evaded pathway-feedback and experienced enhanced PI3K and SRC-family kinase-dependent phosphorylation of Y258XXM, eliciting PI3K activation. hPLEKHS1-mRNA and activating-Y419-phosphorylation of hSRC correlated with PI3K-pathway activity in human prostate cancers. We propose that in PTEN-null cells, receptor-independent, SRC-dependent tyrosine-phosphorylation of PLEKHS1 creates positive-feedback that escapes homeostasis, drives PIP3- signalling and supports tumour progression.

cell biology↗
bioRxiv2017

SETDB1 prevents TET2-dependent activation of IAP retroelements in naïve embryonic stem cells

BackgroundEndogenous retroviruses (ERVs), which are responsible for 10% of spontaneous mouse mutations, are kept under control via several epigenetic mechanisms. The H3K9 histone methyltransferase SETDB1 is essential for ERV repression in embryonic stem cells (ESCs), with DNA methylation also playing an important role. It has been suggested that SETDB1 protects ERVs from TET- dependent DNA demethylation, but the relevance of this mechanism for ERV expression remains unclear. Moreover, previous studies have been performed in primed ESCs, which are not epigenetically or transcriptionally representative of preimplantation embryos.\n\nResultsWe used naive ESCs to investigate the role of SETDB1 in ERV regulation and, in particular, its relationship with TET-mediated DNA demethylation. Naive ESCs show an increased dependency on SETDB1 for ERV silencing when compared to primed ESCs, including at the highly mutagenic intracisternal A particles (IAPs). We found that, in the absence of SETDB1, TET2 activates IAP elements in a catalytic-dependent manner. Surprisingly, however, TET2 does not drive changes in DNA methylation levels at IAPs, suggesting that it regulates these transposons indirectly. Instead, SETDB1 depletion leads to a TET2-dependent loss of H4R3me2s, which is indispensable for IAP silencing during epigenetic reprogramming.\n\nConclusionsOur results demonstrate a novel and unexpected role for SETDB1 in protecting IAPs from TET2-dependent histone arginine demethylation.

genetics↗