T Cell Plasticity in Systemic Lupus Erythematosus Revealed by Large-Scale T Cell Receptor Repertoire and Transcriptome Studies

Objective: We aimed to characterize CD4⁺ T cell plasticity in human systemic lupus erythematosus (SLE) by leveraging T cell receptor (TCR) repertoire features as markers of prior lineage states, integrating TCR and transcriptomic profiling to delineate plasticity patterns and evaluate their association with clinical disease activity. Methods: We used TCR repertoire data as molecular signatures alongside a transcriptomic data set. Using a large-scale ImmuNexUT database of patients with autoimmune disease, including 117 with SLE, we quantified T cell plasticity across 13 fine-grained T cell types. We analyzed 6,392 samples in total. We defined “cell type” and “disease” signatures and evaluated plasticity by correlations between these signatures and by within-donor TCR clonotype overlap. Replication was performed in independent bulk and single-cell cohorts. Results: We identified two orthogonal signatures of the repertoire and transcriptome, the cell type and disease signatures, allowing us to investigate CD4⁺ T cell plasticity comprehensively. Among all possible patterns, the strongest signal was observed between effector Treg cells (eTreg cells) and Th1 cells, and this was replicated in an independent cohort. SLE Th1 cells exhibited Treg-like TCR features and transcriptomic profiles, and eTreg cells showed increased clonotype sharing with Th1 cells compared with healthy controls. The Th1 “Tregness” score positively correlated with SLE disease activity. Conclusion: Our study identifies a Treg-associated Th1 state in human SLE, consistent with Treg cell to Th1 cell plasticity. (Figure presented.).