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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Objective
In 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.
Methods
Two cohorts of drug-naïve 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- VimentinCit64 59-71 or HLA-DRB1*04:04-VimentinCit71 66-78 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.
Results
CD4⁺CXCR5 - PD1 + peripheral helper T cells (Tph), including Cit-vimentin-reactive Tph, CD4⁺CCR7 + 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.
Conclusion
Persistently 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 messages
What is already known on this topic
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Tph and Tfh cells interacting with B cells are implicated in active ACPA+ RA
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Citrullinated (Cit)-vimentin is an important neutrophil extracellular trap-derived target of ACPA
What this study adds
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High 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
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Tph/Tfh and adjacent regulatory T cells surround follicular B-cells in lymphoid aggregates in synovial tissue in non-remission
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Circulating 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
How this study might affect research, practice or policy
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When 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.
