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

Authors

Huizhong Long, Elio Carmona, Mikhail G Dozmorov, Amr H Sawalha

Published in

Arthritis & rheumatology (Hoboken, N.J.). Aug 10, 2026. Epub Aug 10, 2026.

Abstract

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 SLE patients and 12 healthy controls were analyzed by flow cytometry. Single-cell RNA sequencing and TCR sequencing, with and without IFN-α stimulation, in 6 SLE patients and 6 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. IFN-α 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 are HLA-DRB1+. HLA-DRB1 expression on peripheral CD8+ T cells from SLE patients positively correlated with SLEDAI 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 impaired degranulation.

PMID:
42574063
Bibliographic data and abstract were imported from PubMed on 10 Aug 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.