Research Associate University of Pennsylvania, Perelman School of Medicine Philadelphia, Pennsylvania, United States
Disclosure(s):
SUMBUL AFROZ, MSc, PhD: No financial relationships to disclose
Introduction/Rationale: 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.
