Persistent circulating autoreactive PD1⁺TIGIT⁺ peripheral helper T cells reflect synovial lymphoid activity and poor response to conventional disease-modifying anti-rheumatic drugs in early rheumatoid arthritis

Hee, J. Y.; Nel, H. J.; Radetskaya, O.; Antonio-Carreon, G.; Coyle, C.; Suwakulsiri, W.; Soon, M.; Wehr, P.; Tran, M.; Dunlap, G.; Rao, D. A.; Small, A.; Wong, S. W.; Chakradeo, K.; Roch, M.; Lynch, T.; March, L.; Cope, A.; Rossjohn, J.; Wechalekar, M.; Abraham, Y.; Thomas, R.

doi:10.64898/2026.07.28.740434

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bioRxiv · 10.64898/2026.07.28.740434

Persistent circulating autoreactive PD1⁺TIGIT⁺ peripheral helper T cells reflect synovial lymphoid activity and poor response to conventional disease-modifying anti-rheumatic drugs in early rheumatoid arthritis

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Abstract

ObjectiveIn the first year after onset of the autoimmune disease RA (RA), 40-60% do not achieve remission on conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). To understand how autoreactive T cells may contribute to unstable or non-remission, we studied CD4+ T cells, including those recognising citrullinated (Cit) vimentin in participants with RA. MethodsTwo cohorts of drug-naive new-onset participants with RA were treated with csDMARDs. Disease activity score (DAS28-CRP) and peripheral blood (PB) mononuclear cells were collected longitudinally. In HLA-DR-shared epitope+ cohort 1 (n=21), T cells were assessed with a 17-marker spectral flow panel, incorporating HLA-DRB1*04:01/01:01- VimentinCit6459-71 or HLA-DRB1*04:04-VimentinCit7166-78 tetramers. Changes in T cell subsets over time were assessed in remitting and non-remitting participants using a generalized linear mixed model with a negative binomial distribution. In cohort 2 (n=26), the transcriptome of disaggregated synovial tissue (ST) and PB CD4+ T cells were analysed at baseline, and ST biopsy spatial proteomics at baseline and 6 months. ResultsCD4CXCR5-PD1+ peripheral helper T cells (Tph), including Cit-vimentin-reactive Tph, CD4CCR7+CXCR5-PD1+ stem-like Tph and TIGIT+PD1+ Tph were increased with moderate/high DAS28-CRP at any time point. Remission outcome was associated with low CD4 follicular helper T cell (Tfh) and Cit-vimentin-reactive Tfh. In non-remitting participants, Tph/fh infiltrated germinal-centre-like ST aggregates. This decreased in remission. Circulating TIGIT+ Tph genes reflected B lymphoid activation and lymph node egress, while in ST they reflected local differentiation. ConclusionPersistently high circulating TIGIT+ Tph and Tfh, including Cit-vimentin specificities, reflecting antigen-presenting B-cell interactions, are associated with reduced response to csDMARDs in recent-onset RA. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LITph and Tfh cells interacting with B cells are implicated in active ACPA+ RA C_LIO_LICitrullinated (Cit)-vimentin is an important neutrophil extracellular trap-derived target of ACPA C_LI What this study addsO_LIHigh circulating TIGIT+ Tph, Cit-vimentin-autoreactive Tph and Tfh associate with failure to reach remission on conventional synthetic DMARDs within the first year in early HLA-DR shared-epitope+ RA C_LIO_LITph/Tfh and adjacent regulatory T cells surround follicular B-cells in lymphoid aggregates in synovial tissue in non-remission C_LIO_LICirculating TIGIT+ Tph bear a transcriptional signature of lymphoid tissue expansion and lymph node egress as compared to functional differentiation and antigen experience in synovial tissue C_LI How this study might affect research, practice or policyO_LIWhen a remission target is not achieved in HLA-DR shared-epitope+ RA patients during the first year of treatment, high circulating TIGIT+ Tph implicate autoreactive T-B-lymphoid expansion in synovial tissue. C_LI

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Hee, J. Y., Nel, H. J., Radetskaya, O., Antonio-Carreon, G., Coyle, C., Suwakulsiri, W., Soon, M., Wehr, P., Tran, M., Dunlap, G., Rao, D. A., Small, A., Wong, S. W., Chakradeo, K., Roch, M., Lynch, T., March, L., Cope, A., Rossjohn, J., Wechalekar, M., Abraham, Y., Thomas, R.. 2026-07-30. Persistent circulating autoreactive PD1⁺TIGIT⁺ peripheral helper T cells reflect synovial lymphoid activity and poor response to conventional disease-modifying anti-rheumatic drugs in early rheumatoid arthritis. https://doi.org/10.64898/2026.07.28.740434

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