Novel self-amplificatory loop between T cells and tenocytes as a driver of chronicity in tendon disease

Garcia-Melchor, E., Cafaro, G., MacDonald, L. , Crowe, L. A.N., Sood, S., McLean, M., Fazzi, U., McInnes, I. B. , Akbar, M. and Millar, N. L. (2021) Novel self-amplificatory loop between T cells and tenocytes as a driver of chronicity in tendon disease. Annals of the Rheumatic Diseases, 80(8), pp. 1075-1085. (doi: 10.1136/annrheumdis-2020-219335) (PMID:33692018)

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Abstract

Objectives: Increasing evidence suggests that inflammatory mechanisms play a key role in chronic tendon disease. After observing T cell signatures in human tendinopathy, we explored the interaction between T cells and tendon stromal cells or tenocytes to define their functional contribution to tissue remodelling and inflammation amplification and hence disease perpetuation. Methods: T cells were quantified and characterised in healthy and tendinopathic tissues by flow cytometry (FACS), imaging mass cytometry (IMC) and single cell RNA-seq. Tenocyte activation induced by conditioned media from primary damaged tendon or interleukin-1β was evaluated by qPCR. The role of tenocytes in regulating T cell migration was interrogated in a standard transwell membrane system. T cell activation (cell surface markers by FACS and cytokine release by ELISA) and changes in gene expression in tenocytes (qPCR) were assessed in cocultures of T cells and explanted tenocytes. Results: Significant quantitative differences were observed in healthy compared with tendinopathic tissues. IMC showed T cells in close proximity to tenocytes, suggesting tenocyte–T cell interactions. On activation, tenocytes upregulated inflammatory cytokines, chemokines and adhesion molecules implicated in T cell recruitment and activation. Conditioned media from activated tenocytes induced T cell migration and coculture of tenocytes with T cells resulted in reciprocal activation of T cells. In turn, these activated T cells upregulated production of inflammatory mediators in tenocytes, while increasing the pathogenic collagen 3/collagen 1 ratio. Conclusions: Interaction between T cells and tenocytes induces the expression of inflammatory cytokines/chemokines in tenocytes, alters collagen composition favouring collagen 3 and self-amplifies T cell activation via an auto-regulatory feedback loop. Selectively targeting this adaptive/stromal interface may provide novel translational strategies in the management of human tendon disorders.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Cafaro, Dr Giacomo and MacDonald, Lucy and Millar, Professor Neal and Sood, Dr Shatakshi and Akbar, Mr Moeed and McLean, Michael and Fazzi, Mr Umberto
Authors: Garcia-Melchor, E., Cafaro, G., MacDonald, L., Crowe, L. A.N., Sood, S., McLean, M., Fazzi, U., McInnes, I. B., Akbar, M., and Millar, N. L.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Annals of the Rheumatic Diseases
Publisher:BMJ Publishing Group
ISSN:0003-4967
ISSN (Online):1468-2060
Published Online:10 March 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Annals of the Rheumatic Diseases 80(8): 1075-1085
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301515Damage mechanisms in tendon diseaseNeal MillarMedical Research Council (MRC)MR/R020515/1III - Immunology
173463HMGB1: a key damage mediator in tendinopathyNeal MillarVersus Arthritis (ARTRESUK)21346III - Immunology