TCRß sequencing reveals spatial and temporal evolution of clonal CD4 T cell responses in a breach of tolerance model of inflammatory arthritis

Al Khabouri, S., Benson, R. A. , Prendergast, C. T., Gray, J. I., Otto, T. D. , Brewer, J. M. and Garside, P. (2021) TCRß sequencing reveals spatial and temporal evolution of clonal CD4 T cell responses in a breach of tolerance model of inflammatory arthritis. Frontiers in Immunology, 12, 669856. (doi: 10.3389/fimmu.2021.669856) (PMID:33986757) (PMCID:PMC8110912)

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Abstract

Effective tolerogenic intervention in Rheumatoid Arthritis (RA) will rely upon understanding the evolution of articular antigen specific CD4 T cell responses. TCR clonality of endogenous CD4 T cell infiltrates in early inflammatory arthritis was assessed to monitor evolution of the TCR repertoire in the inflamed joint and associated lymph node (LN). Mouse models of antigen-induced breach of self-tolerance and chronic polyarthritis were used to recapitulate early and late phases of RA. The infiltrating endogenous, antigen experienced CD4 T cells in inflamed joints and LNs were analysed using flow cytometry and TCRβ sequencing. TCR repertoires from inflamed late phase LNs displayed increased clonality and diversity compared to early phase LNs, while inflamed joints remained similar with time. Repertoires from late phase LNs accumulated clones with a diverse range of TRBV genes, while inflamed joints at both phases contained clones expressing similar TRBV genes. Repertoires from LNs and joints at the late phase displayed reduced CDR3β sequence overlap compared to the early disease phase, however the most abundant clones in LNs accumulate in the joint at the later phase. The results indicate CD4 T cell repertoire clonality and diversity broadens with progression of inflammatory arthritis and is first reflected in LNs before mirroring in the joint. These observations imply that antigen specific tolerogenic therapies could be more effective if targeted at earlier phases of disease when CD4 T cell clonality is least diverse.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Gray, Joshua and Prendergast, Dr Catriona and Benson, Dr Robert and Garside, Professor Paul and Brewer, Professor James and Otto, Dr Thomas and Al Khabouri, Shaima Mazin Jawad
Authors: Al Khabouri, S., Benson, R. A., Prendergast, C. T., Gray, J. I., Otto, T. D., Brewer, J. M., and Garside, P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Frontiers in Immunology
Publisher:Frontiers Media
ISSN:1664-3224
ISSN (Online):1664-3224
Copyright Holders:Copyright © 2021 Al Khabouri, Benson, Prendergast, Gray, Otto, Brewer and Garside
First Published:First published in Frontiers in Immunology 12:669856
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
303229RACE RenewalIain McInnesVersus Arthritis (ARTRESUK)NW/22072III - Immunology
166480Defining the Role of Cell Migration in the Initiation and Regulation of Pathogenesis in Inflammatory ArthritisPaul GarsideVersus Arthritis (ARTRESUK)MP/19788III - Immunology
190682Rheumatoid Arthritis Centre of Excellence (RACE - Towards a Cure)Iain McInnesVersus Arthritis (ARTRESUK)MP20298III - Immunology
301069Rheuma Tolerance for CureIain McInnesEuropean Commission (EC)777357III - Immunology