Biology subjects

Kimber, R.

Publications and source records attributed to Kimber, R..

3 recordsLinked to original sources

bioRxiv2025

RNA helicase DDX1 regulates germinal centre selection and affinity maturation by promoting tRNA ligase activity

Clonal expansion of antigen-specific B-cells defines effective germinal centre responses and is key for the generation of high-affinity antibodies. While positive selection in germinal centres has been associated with anabolic metabolism and cell growth, the downstream drivers of B-cell proliferation are not well understood. Here we report that the RNA helicase DDX1 is required for germinal centre maturation and accrual of dark-zone cellularity. Upon interaction with T-follicular helper cells, DDX1-deficient B-cells upregulate c-MYC but do not clonally expand. We show that positive selection is coupled with an increase in mRNA translation, that is dependent on DDX1. DDX1 endows B-cells with the protein biosynthetic capability that is required for rapid cell proliferation. It does so by modulating the activity of the tRNA ligase complex and tRNA splicing. Our data reveal that mRNA translation efficiency is a key determinant of B-cell fitness during germinal centre responses.

immunology↗

bioRxiv2024

Mating-compatibility genes employed as diagnostic markers to identify novel incursions of the myrtle rust pathogen Austropuccinia psidii

Austropuccinia psidii is the causal agent of myrtle rust in over 480 species within the family Myrtaceae. Lineages of A. psidii are structured by host in its native range, and some have success on new-encounter hosts. For example, the pandemic biotype has spread beyond South America, and proliferation of other lineages is an additional risk to biodiversity and industries. Efforts to manage A. psidii incursions, including lineage differentiation, relies on variable microsatellite markers. Testing these markers is time-consuming and complex, particularly on a large scale. We designed a novel diagnostic approach targeting the fungal mating-type HD (homeodomain) transcription factor locus to address these limitations. The HD locus (bW1/2-HD1 and bE1/2-HD2) is highly polymorphic, facilitating clear biological predictions about its inheritance from founding populations. To be considered the same lineage, all four HD alleles must be identical. Our lineage diagnostics relies on PCR amplification of the HD locus in different genotypes of A. psidii followed by amplicon sequencing using Oxford Nanopore Technologies (ONT) and comparative analysis. The lineage-specific assay was validated on four isolates with existing genomes, uncharacterized isolates, and directly from infected leaf material. We reconstructed HD alleles from amplicons and confirmed their sequence identity relative to their reference. Genealogies using HD alleles confirmed the variations at the HD loci among lineages/isolates. Our study establishes a robust diagnostic tool, for differentiating known lineages of A. psidii based biological predictions. This tool holds promise for detecting new pathogen incursions and can be refined for broader applications, including air-sample detection and mixed-isolate infections.

plant biology↗

bioRxiv2019

A novel antibody targeting ICOS increases intratumoural cytotoxic to regulatory T cell ratio and induces tumour regression.

The immunosuppressive tumour microenvironment constitutes a significant hurdle to the response to immune checkpoint inhibitors. Both soluble factors and specialised immune cells such as regulatory T cells (TReg) are key components of active intratumoural immunosuppression. Previous studies have shown that Inducible Co-Stimulatory receptor (ICOS) is highly expressed in the tumour microenvironment, especially on TReg, suggesting that it represents a relevant target for preferential depletion of these cells. Here, we used immune profiling of samples from tumour bearing mice and cancer patients to characterise the expression of ICOS in different tissues and solid tumours. By immunizing an Icos knockout transgenic mouse line expressing antibodies with human variable domains, we selected a fully human IgG1 antibody called KY1044 that binds ICOS from different species. Using KY1044, we demonstrated that we can exploit the differential expression of ICOS on T cell subtypes to modify the tumour microenvironment and thereby improve the anti-tumour immune response. We showed that KY1044 induces sustained depletion of ICOShigh TReg cells in mouse tumours and depletion of ICOShigh T cells in the blood of non-human primates, but was also associated with secretion of pro-inflammatory cytokines from ICOSlow TEFF cells. Altogether, KY1044 improved the intratumoural TEFF:TReg ratio and increased activation of TEFF cells, resulting in monotherapy efficacy or in synergistic combinatorial efficacy when administered with the immune checkpoint blocker anti-PD-L1. In summary, our data demonstrate that targeting ICOS with KY1044 can favourably alter the intratumoural immune contexture, promoting an anti-tumour response.

cancer biology↗