Self-reactive CD4+ T cells display diverse differentiation in health and gain stem-like features in rheumatoid arthritis 2308930

Abstract Introduction Self-reactive T cells have long been associated with autoimmune diseases, yet they are also a physiological component of the peripheral immune repertoire in healthy individuals. Beyond regulatory T cells, little is known about the phenotypic and functional features that restrain self-reactive T cells in healthy and how these features change in disease, which is critical for understanding immune tolerance failure in rheumatoid arthritis (RA). Methods We used a ferritin-based peptide—MHC II multimer platform (spheromers) to capture rare self-reactive T cells and performed high-dimensional phenotypic analyses comparing them with SARS-CoV-2 spike- and influenza hemagglutinin (HA)-specific T cells in pre-2021 blood samples from healthy donors (HD). Phenotypic and functional comparisons between HD and RA patients were assessed using in vitro T cell and antigen-matured dendritic cell co-culture assays. Results Spheromers captured significantly more self-reactive cells than conventional tetramers. In HD, self-reactive CD4+ T cells displayed predominantly memory phenotypes enriched for Tregs and CXCR5⁻PD-1+TIGIT+ Tph-like cells, distinct from pre-exposure spike- and post-exposure HA-specific populations. To examine pathologic changes, we identified self-reactive T cells in RA patients and compared them to HD. Although overall frequencies were similar, self-reactive T cells in RA were enriched for naïve-like subsets, suggesting increased stemness. Consistent with this, naïve T cells responded to the autoantigen citrullinated +-Enolase. +-Enolase—reactive T cells from the naïve pool exhibited greater differentiation plasticity than non-naive counterparts and proliferated more robustly, generating proinflammatory TIGIT+ cytokine-producing cells in RA compared to HD. Conclusion Together, these data reveal diverse states of self-reactive CD4+ T cells in health and identify stem-like self-reactive T cells in RA that give rise to inflammatory progeny and may sustain pathologic self-reactivity. Funding Source n/a Topic Categories Basic Autoimmunity (BA)