Kirkham, B. W. | bioRxiv Science

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↗