Type I interferon drives dysfunction of a distinct CD8+ HLA-DRB1+ T cell subset in systemic lupus erythematosus.

Objective: Systemic lupus erythematosus (SLE) is characterized by persistent type I interferon (IFN) signaling and adaptive immune dysregulation. We previously identified hypomethylation of Methods: Peripheral blood CD8+ T cells from SLE patients and healthy controls were analyzed by flow cytometry to assess differentiation and effector functions. Single-cell RNA sequencing and TCR sequencing, with and without IFN-α stimulation, were used to assess transcriptional heterogeneity, exhaustion, senescence, and cytotoxicity. Results: CD8+ HLA-DRB1+ T cells were enriched within effector memory and terminally differentiated CD8+ T cells and were significantly expanded within the effector memory compartment in SLE compared to healthy controls. These cells displayed paradoxical features of cytotoxic activation, proliferative potential, exhaustion, and senescence. Compared to healthy controls, lupus CD8+ HLA-DRB1+ T cells exhibited increased exhaustion, reduced cytotoxicity, and impaired viral defense pathways. IFN-α treatment enhanced IFN-γ responses in lupus CD8+ HLA-DRB1+ T cells and exacerbated exhaustion and senescence. Despite upregulation of cytotoxic gene expression, IFN-α reduced CD107a surface mobilization, indicating impaired degranulation. Analysis of lupus nephritis datasets revealed that most kidney-infiltrating CD8+ T cells express HLA-DRB1. Conclusion: CD8+ HLA-DRB1+ T cells represent a cytotoxic yet dysfunctional effector memory population expanded in SLE. Type I IFN drives this paradoxical state by promoting exhaustion and impaired degranulation, highlighting a potential therapeutic axis in SLE.