Biology subjects

Gordon, C. L.

Publications and source records attributed to Gordon, C. L..

5 recordsLinked to original sources

bioRxiv2026

Immunopeptidomics reveals peptide antigens preferentially presented in psoriasis lesional skin of HLA-C*06:02 carriers

BackgroundHuman leukocyte antigen (HLA)-C*06:02 is a major genetic risk factor for psoriasis and understanding the HLA-C*06:02-presented peptide antigen repertoire (immunopeptidome) in the skin of patients is crucial for identifying autoantigens. Yet, no skin immunopeptidome data from patients stratified by their HLA-C*06:02 status exists. ObjectiveWe analysed biopsies from lesional and non-lesional skin of patients with psoriasis vulgaris (n=12), guttate psoriasis (n=8), or from skin of healthy controls (n=16). MethodsHLA class I and class II peptide complexes were isolated by serial immunoprecipitation and HLA-bound peptides identified by liquid chromatography-tandem mass spectrometry. HLA-C*06:02 genotyping was performed by polymerase chain reaction. ResultsOver 99,000 non-redundant peptide ligands were identified across all samples. Substantially more HLA class I and class II peptides were detected in lesional psoriatic skin compared to matched non-lesional and healthy skin. Three peptides predicted to bind HLA-C*06:02, including MRASSFLIV from the known psoriasis marker peptidase inhibitor 3 (PI3), were identified in all lesions of HLA-C*06:02-positive patients but were rarely detected or absent in HLA-C*06:02-negative patient lesional skin and not detected at all in unaffected skin. Keratinocyte differentiation-associated protein (KRTDAP) was a notable source of lesion-specific HLA class II ligands contributing three out of six peptides detected in more than half of the lesional samples. ConclusionActive psoriatic lesions display an altered and expanded immunopeptidome compared to unaffected skin. We have identified numerous unreported, lesion-specific HLA-bound peptides and their source proteins. These findings offer insights into the pathobiology of psoriasis and provide a resource for future functional studies. CAPSULE SUMMARYA selection of immunopeptides is presented exclusively in lesional skin of HLA-C*06:02+ patients with psoriasis that may represent antigenic drivers of disease.

immunology↗

bioRxiv2024

Selective regulation of IFN-γ and IL-4 co-producing unconventional T cells by purinergic signalling

Unconventional T cells, including mucosal-associated invariant T (MAIT), natural killer T (NKT), and gamma-delta T ({gamma}{delta}T) cells, comprise distinct T-bet+, IFN-{gamma}+ and ROR{gamma}t+, IL-17+ subsets which play differential roles in health and disease. NKT1 cells are susceptible to ARTC2-mediated P2X7 receptor (P2RX7) activation, but the effects on other unconventional T-cell types are unknown. Here, we show that MAIT, {gamma}{delta}T, and NKT cells express P2RX7 and are sensitive to P2RX7-mediated cell death. Mouse peripheral T-bet+ MAIT1, {gamma}{delta}T1, and NKT1 cells, especially in liver, co-express ARTC2 and P2RX7, which can be further upregulated by retinoic acid. Blocking ARTC2 or inhibiting P2RX7 protected MAIT1, {gamma}{delta}T1, and NKT1 cells from cell death, enhanced their survival in vivo, and increased the number of IFN-{gamma}-secreting cells without affecting IL-17 production. Importantly, this revealed the existence of IFN-{gamma} and IL-4 co-producing unconventional T-cell populations normally lost upon isolation due to ARTC2/P2RX7-induced death. Administering extracellular NAD in vivo activated this pathway, depleting P2RX7-sensitive unconventional T cells. Our study reveals ARTC2/P2RX7 as a common regulatory axis modulating the unconventional T-cell compartment, affecting the viability of IFN-{gamma}- and IL-4-producing T cells, offering important insights to facilitate future studies into how these cells can be regulated in health and disease.

immunology↗

bioRxiv2023

mTOR signaling controls the formation of smooth muscle cell-derived intimal fibroblasts during vasculitis.

The excessive accumulation of fibroblasts within the intimal layer of inflamed vessels is a feared complication of vasculitis, which can lead to arterial stenosis and ischemia. In this study, we have investigated how such intimal fibroblasts develop during Kawasaki Disease (KD), a paediatric vasculitis typically involving the coronary arteries. By performing lineage tracing studies in a murine model of KD, we reveal that vasculitis-induced intimal fibroblasts develop independently of both adventitial fibroblasts and endothelial cells, and instead derive from smooth muscle cells (SMCs). Notably, the emergence of SMC-derived intimal fibroblasts - in both mice and in patients with KD, Takayasus arteritis and Giant Cell arteritis - coincided with their activation of the mechanistic target of rapamycin (mTOR) signalling pathway. Moreover, the genetic deletion of mTOR signalling in SMCs abrogated the emergence of intimal fibroblasts, demonstrating that mTOR is an intrinsic and essential regulator of vasculitis-induced, SMC-derived intimal fibroblasts. Collectively these findings provide molecular insight into the pathogenesis of arterial stenosis and identify mTOR as a therapeutic target to prevent adverse vascular remodelling in vasculitis.

cell biology↗

bioRxiv2021

Early immune pressure imposed by tissue resident memory T cells sculpts tumour evolution in non-small cell lung cancer

Tissue-resident memory T cells (TRM) provide immune defence against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts TRM activation and how the immune pressure exerted by TRM affects developing tumours in humans. We performed deep profiling of lung cancers arising in never-smokers (NS) and ever-smokers (ES), finding evidence of enhanced TRM immunosurveillance in ES lung. Only tumours arising in ES patients underwent clonal immune escape, even when evaluating cancers with similar tumour mutational burden to NS patients, suggesting that the timing of immune pressure exerted by TRM is a critical factor in the evolution of tumour immune evasion. Tumours grown in T cell quiescent NS lungs displayed little evidence of immune evasion and had fewer neoantigens with low diversity, paradoxically making them amenable to treatment with agonist of the costimulatory molecule, ICOS. These data demonstrate local environmental insults enhance TRM immunosurveillance of human tissue, shape the evolution of tumour immunogenicity and that this interplay informs effective immunotherapeutic modalities.

cancer biology↗

bioRxiv2018

Multimodal music perception engages motor prediction: a TMS study

Cortico-spinal excitability (CSE) in humans measured with Transcranial Magnetic Stimulation (TMS) is generally increased by the perception of other peoples actions. This perception can be unimodal (visual or auditory) or multimodal (visual and auditory). The increase in TMS-measured CSE is typically prominent for muscles involved in the perceived action (muscle specificity). There are two main classes of accounts for this phenomenon. One suggests that the motor system mirrors the actions that the observer perceives (the resonance account). The other suggests that the motor system predicts the actions that the observer perceives (the predictive account). To test these accounts (which need not be mutually exclusive), subjects were presented with four versions of three-note piano sequences: sound only, sight only, audiovisual, and audiovisual with sound lagging behind while CSE was measured in two hand muscles. Muscle specificity did not interact with modality in the flexor digiti minimi (FDM), but was reliably higher for the first dorsal interosseous (FDI) while subjects perceived the audiovisual version of the three-note piano sequences with sound lagging behind. Since this version of the three-note piano sequences is the only one that overtly violates experience-based expectations, this finding supports predictive coding accounts of motor facilitation during action perception.

neuroscience↗