Type I Interferon Drives Dysfunction of a Distinct CD8⁺ HLA-DRB1⁺ T Cell Subset in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is characterized by type I interferon (IFN) signaling and adaptive immune dysregulation. We previously identified hypomethylation of HLA-DRB1 and STAT1 in SLE CD8⁺ T cells, enabling aberrant IFN-driven HLA-DRB1 expression and expansion of a distinct CD8⁺ T cell subset. This study characterized CD8⁺ HLA-DRB1⁺ T cells in lupus.

Peripheral blood CD8⁺ T cells from 11 patients with SLE and 12 healthy controls were analyzed by flow cytometry. Single-cell RNA sequencing and T cell receptor sequencing, with and without IFNα stimulation, in six patients with SLE and six matched healthy controls assessed transcriptional heterogeneity, exhaustion, senescence, and cytotoxicity.

CD8⁺ HLA-DRB1⁺ T cells were enriched within effector memory, CD45RA⁺ effector memory, and proliferative CD8⁺ T cells and were significantly expanded within the effector memory and proliferative compartment in SLE compared to healthy controls. These cells displayed paradoxical features of cytotoxicity, proliferation, exhaustion, and senescence. Compared to healthy controls, lupus CD8⁺ HLA-DRB1⁺ T cells exhibited increased exhaustion, reduced cytotoxicity, and impaired antiviral pathways. IFNα enhanced IFNγ responses in lupus CD8⁺ HLA-DRB1⁺ T cells and exacerbated exhaustion and senescence. Despite up-regulation of cytotoxic gene expression, IFNα reduced CD107a surface mobilization, indicating impaired degranulation. Analysis of lupus nephritis data sets revealed that most kidney-infiltrating CD8⁺ T cells are HLA-DRB1⁺. HLA-DRB1 expression on peripheral CD8⁺ T cells from patients with SLE positively correlated with Systemic Lupus Erythematosus Disease Activity Index scores.

CD8⁺ HLA-DRB1⁺ T cells represent a dysfunctional effector memory and proliferative population expanded in SLE. Type I IFN drives this paradoxical state by promoting exhaustion and impairing degranulation.