Characterization of CD4+ T cells expressing an elevated interferon-stimulated gene signature in SLE patients

Abstract

Abstract The type I interferon (IFN) signaling pathway plays a key role in Systemic Lupus Erythematosus (SLE) pathology, and a majority of patients display elevated expression levels of interferon-stimulated genes (ISGs) in the peripheral blood. However, it is unclear which immune cells are responding to IFN to drive disease pathology. We compared the ISG signatures of cell types sorted from peripheral blood of IFNβ-treated relapsing-remitting multiple sclerosis (RRMS) patients with those of SLE patients. While systemic IFNβ treatment stimulated ISG expression in the monocytes and neutrophils of RRMS patients, the ISG signature in SLE patients was primarily detected in CD4+ T and B cells. This suggests these cells may be exposed to higher levels of IFN in microenvironments of inflammation within SLE patients, such as upon interaction with APC presenting SLE antigens. We hypothesize that a subset of primarily antigen-specific CD4+ T cells expand and express ISGs during SLE disease activity, and that these cells and their signature pathways can serve as disease biomarkers and therapeutic targets. To examine ISG expression by CD4+ T cells in SLE, we compared the expression of several ISG-correlated surface markers between high- and low-IFN score patients and healthy controls. Subsets of CD4+ T cells in high-IFN score patients expressed elevated levels of PD1, CD66a, and OX40, while the majority of cells expressed a similar level as cells in healthy controls. This suggests that only a small subset of CD4+ T cells is activated by localized IFN sources and is involved in SLE pathology. We have further characterized PD1+, OX40+ CD66a+, and SLE-specific memory CD4+ T cells by RNAseq and flow cytometry.