Background: Recognition of self-peptides by autoreactive CD4+ T-cells drives systemic autoimmunity. While Sjögren’s syndrome (SjS) and systemic sclerosis (SSc) are both responsive to anti-nuclear antigens (ANAg), local and systemic molecular mechanisms driving distinct tissue pathology remain enigmatic.

Objectives: We aimed to analyze autoreactive CD4+ T-cells across affected tissues and locoregional lymph nodes to identify mechanisms differentiating SjS and SSc, advancing insights into systemic autoimmunity and tissue-specific pathology for personalized therapies.

Methods: 3’-fluoro-3’-deoxy-thymidine [18F] FLT PET scans followed by ultrasound-guided biopsies of PET-avid and PET-negative nodes identified reactive lymph nodes (LNs) in SjS (n=10) and SSc (n=10) patients, along with matched affected tissues (salivary gland for SjS, skin for SSc) (Figure 1A). Ex vivo T-cell stimulation assays and multi-modal single-cell analyses (transcriptome, proteome, TCR sequencing) identified ANAg (SSA/SSB and scl70)-reactive CD4+ T-cells in patients’ blood (n=45 SSc, n=37 SjS), LNs and affected tissues (n=10). Flow cytometry and multiplex immunofluorescence validated and mapped the spatial localization of autoreactive cells.

Results: In both SjS and SSc, memory ANAg-reactive T-cell clones were expanded in blood and correlated with disease severity (Figure 1B). Some clones were shared across blood, lymph nodes (LNs), and affected tissues. In SjS, PET-avid LNs and blood showed increased SSA/B-reactive Th2, Th17, follicular, and peripheral T-helper populations compared to PET-negative LNs. In SSc, PET-avid LNs and blood contained primarily scl70-reactive peripheral CD4+ T-cells and few other effector CD4+ T-cells. Notably, a novel CD4+TRAIL+ T-cell population with an interferon stimulated gene signature (ISG) was expanded in PET-avid LNs of SSc patients (Figure 1C). Functionally, this unique T cell population suppressed antigen-presenting cell activation, reducing effector T-helper cell-driven plasma cell formation and autoantibody production (Figure 1D). Strikingly, elevated serum TRAIL levels were linked to milder disease in SSc, highlighting their potentially protective role.

Conclusion: Our data reveal disease-specific autoreactive T-cell immunity. Naive and innate-like CD4+ TRAIL+ ISG ANAg-reactive T-cells differentially regulate ANAg responses in SjS and SSc. The TRAIL-DR4 axis restricts autoantibody production, offering a potential target for developing tolerogenic therapies for systemic autoimmune diseases.

Figure 1.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.