Biology subjects

Taams, L. S.

Publications and source records attributed to Taams, L. S..

5 recordsLinked to original sources

bioRxiv2026

Refinement of the Pathogenic T Cell Receptor Motif Suggests Type 17 CD8+ T Cells Initiate HLA-B*27-associated Autoimmunity

Human leukocyte antigen B*27 (HLA-B*27) is a major risk factor for autoimmune diseases such as axial spondyloarthritis (axSpA), acute anterior uveitis (AAU), and psoriatic arthritis (PsA). HLA-B*27 presents bacterial and self-antigens to disease-associated CD8+ T cells, however, how this leads to a pathogenic IL-17-mediated disease remains unclear. We performed mutational experiments in an established disease-associated TCR and demonstrated that the pathogenic motif encompasses a wider range of TCR sequences than previously appreciated. We next leveraged computational pairing of alpha/beta TCR sequencing (TCR-seq) to demonstrate that the broadened pathogenic motif distinguishes axSpA and AAU patients from healthy controls. Paired single-cell RNA sequencing and single-cell TCR sequencing datasets demonstrated that the pathogenic cells have a distinct transcriptional signature. We find a coupling of pathogenic TCRs to this transcriptional signature in public datasets from axSpA and PsA joint fluid and AAU ocular fluid. Finally, we detect the pathogenic CD8+ T cells in the gut and demonstrate that they express a Type 17 program. Our findings suggest that HLA-B*27+ axSpA, AAU, and PsA are initiated by HLA-B*27-restricted pathogenic CD8+ T cells that undergo Type 17 differentiation in response to intestinal antigens.

immunology↗

bioRxiv2024

Blockade of rheumatoid arthritis synovial fluid-induced sensory neuron activation by JAK inhibitors

ObjectiveClinical studies suggest that compared to anti-TNF treatment, JAK inhibitors (JAKi) are superior in reducing pain in rheumatoid arthritis (RA). The underlying mechanisms for this observation are still unknown. Sensory neurons transmit noxious signals from inflamed joints to the central nervous system, where a pain percept is generated. We investigated whether JAKi exert direct effects on sensory neurons. MethodsIn-house and public RNA sequencing datasets of sensory neurons were analysed for relevant JAK/STAT and cytokine-receptor gene expression. Human induced pluripotent stem cell (IPSC)-derived sensory neurons were stimulated with serum and synovial fluid (SF) from individuals with RA, or with selected cytokines that were found in RA SF by Luminex. Phosphorylation of STAT3 (pSTAT3) was assessed by Western blot. Sensory neuron activation was examined by recording neuronal firing using multi-electrode array and measuring expression levels of pain-relevant genes with STAT3-binding sites. ResultsCell-free RA synovial fluid induced pSTAT3 in IPSC-derived sensory neurons, an effect which was completely blocked by the JAKi tofacitinib. Compared to paired serum, RA SF was enriched for the JAK/STAT cytokines IL-6, IL-11, LIF, IFN-alpha and IFN-beta, with their requisite receptors present on sensory neurons. Stimulation of IPSC- derived sensory neurons with these recombinant cytokines recapitulated pSTAT3 induction in these cells. Furthermore, IL-6+sIL-6R or LIF upregulated expression of pain-relevant genes which was blocked by tofacitinib. Finally, we provided evidence that LIF can induce neuronal sensitisation. ConclusionOur data indicate that JAKi can act directly on sensory neurons, providing a potential mechanistic explanation for their suggested superior analgesic properties.

immunology↗

bioRxiv2024

Clonal sharing of CD8+ T-cells links skin and joint inflammation in psoriatic arthritis

We hypothesised that skin and joint inflammation in psoriatic arthritis (PsA) is linked in terms of CD8+ T-cell phenotype and clonality. We employed scRNAseq to directly compare the transcriptional signature and T-cell receptor repertoire of memory T-cells from paired skin and synovial tissue and/or fluid from patients with PsA. We identified an enrichment of type-17 CD8+ tissue-resident memory (TRM) T-cells in both skin and joint, with a stronger IL-17 signature in the skin than the joint. Several T-cell clones were shared between the skin and joint and these shared clones tended to have the same signature at both sites, characterised by increased expression of genes associated with a cytotoxic, tissue-resident phenotype. Our findings support the hypothesis that skin and joint inflammation in PsA is linked in terms of T-cell clonality and raises the possibility that specific T-cells migrate between these compartments to propagate inflammation across both sites.

immunology↗

bioRxiv2022

Phenotypic, functional and molecular characterisation of human in vitro-generated IL-17A+ CD8+ T-cells

IL-17A+ CD8+ T-cells, often referred to as Tc17 cells, have been identified at sites of inflammation in several immune-mediated inflammatory diseases including psoriasis and spondyloarthritis. Whilst much of our understanding of IL-17A+ CD8+ T-cells has been discerned from murine studies, human IL-17A+ CD8+ T-cells remain less-well characterised. We optimised an in vitro polarisation protocol to expand human IL-17A+ CD8+ T-cells from PBMC or bulk CD8+ T-cell populations for phenotypic and functional assessment. We show that T-cell activation in the presence of IL-1{beta} and IL-23 significantly increased the frequencies of IL-17A+ CD8+ T-cells, which was not further enhanced by the addition of IL-6, IL-2 or anti-IFN{gamma} mAb. In vitro-generated IL-17A+ CD8+ T-cells from healthy donors displayed a distinct type-17 profile compared with IL-17A- CD8+ T-cells, as defined by transcriptional signature (IL17A, IL17F, RORC, RORA, MAF, IL23R, CCR6, CXCR6); high surface expression of CCR6 and CD161; and polyfunctional production of IL-17A, IL-17F, IL-22, IFN{gamma}, TNF and GM-CSF. A significant proportion of in vitro-induced IL-17A+ CD8+ T-cells expressed TCRV7.2 and bound MR1 tetramers, indicative of a MAIT CD8+ T-cell population. Using an IL-17A secretion assay, we demonstrate that the in vitro-generated IL-17A+ CD8+ T-cells were biologically functional and induced pro-inflammatory IL-6 and IL-8 production by synovial fibroblasts from patients with psoriatic arthritis. Collectively, we report an in vitro culture system to expand IL-17A+ CD8+ T-cells and further characterise their phenotype, transcriptional regulation and functional relevance to human health and disease.

immunology↗

bioRxiv2020

Human milk extracellular vesicles target nodes in interconnected signalling pathways that enhance oral epithelial barrier function and dampen immune responses

Maternal milk is natures first functional food. It plays a crucial role in the development of the infants gastrointestinal (GI) tract and the immune system. Extracellular vesicles (EVs) are a heterogeneous population of lipid bilayer enclosed vesicles released by cells for intercellular communication and are a component of milk. Recently, we discovered that human milk EVs contain a unique proteome compared to other milk components. Here, we show that physiological concentrations of milk EVs support epithelial barrier function by increasing cell migration via the p38 MAPK pathway. Additionally, milk EVs inhibit agonist-induced activation of endosomal Toll like receptors TLR3 and TLR9. Furthermore, milk EVs directly inhibit activation of CD4+ T cells by temporarily suppressing T cell activation without inducing tolerance. We show that milk EV proteins target key hotspots of signalling networks that can modulate cellular processes in various cell types of the GI tract.

immunology↗