Tofacitinib inhibits CD4 T cell polarisation to Th1 during priming thereby leading to clinical impact in a model of experimental arthritis

Bejad, M., Bonilha, C. S., McInnes, I. B. , Garside, P. and Benson, R. A. (2021) Tofacitinib inhibits CD4 T cell polarisation to Th1 during priming thereby leading to clinical impact in a model of experimental arthritis. Clinical and Experimental Rheumatology, (PMID:34494958) (Early Online Publication)

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Publisher's URL: https://www.clinexprheumatol.org/abstract.asp?a=17362

Abstract

Objectives: Janus kinases (JAK) are key cell membrane orientated tyrosine kinases that regulate inflammatory responses by transducing signals received by cytokine receptors that directly influence the polarisation and function of Th cells. Tofacitinib is a pan-JAK inhibitor approved for the treatment of RA. In this study, we explored the effects of tofacitinib in the outcomes of CD4+ T cell-dendritic cell (DC) interactions and their impact in autoimmune arthritis. Methods: The impact of tofacitinib in CD4+ T cell outcomes during priming or re-activation were analysed using antigen-specific in vitro and/or in vivo systems. A breach of self-tolerance model of arthritis was used to investigate the effects of tofacitinib in the outcomes of newly primed and antigen experienced CD4+ T cells. Results: Tofacitinib inhibited Th1 polarisation during priming both in vitro and in vivo. In vitro, impaired T-bet expression and IFN-y production persisted upon secondary antigen challenge. Tofacitinib treatment during re-activation in vitro did not impact differentiation of antigen experienced CD4+ T cell towards Th1 phenotype. Moreover, JAK inhibition limited adaptive immune responses mediated by recently activated T cells and subsequent breach of self-tolerance in experimental arthritis. Conclusions: Our findings provide a novel mode of action for tofacitinib, demonstrating a potential therapeutic utility via homeostatic immune restoration in very early autoimmune arthritis.

Item Type:Articles
Status:Early Online Publication
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Bonilha, Caio and Benson, Dr Robert and Garside, Professor Paul
Authors: Bejad, M., Bonilha, C. S., McInnes, I. B., Garside, P., and Benson, R. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Clinical and Experimental Rheumatology
Publisher:Pacini Editore Srl
ISSN:0392-856X
ISSN (Online):1593-098X
Published Online:07 September 2021

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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