Pathogenic role of IFNγ from activated CD4+ T cells in lupus model mice induced by topical treatment with toll-like receptor agonist imiquimod.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement. It is known that cytokines produced from activated CD4+ T cells play a pivotal role in the development of SLE; however, the details of pathological processes remain unclear. The purpose of this study is to elucidate the role of activated CD4+ T cells on the pathogenesis of lupus using SLE murine models induced by toll like receptor 7 agonist imiquimod (IMQ). Lupus was induced in wild-type (WT) and interferon γ (IFNγ)-deficient (IFNγ-/-) mice by topical IMQ treatment. Splenic T and B cell subsets were analyzed by flow cytometry. CD4+ T cells and B cells were isolated for co-culture to assess B cell differentiation and IgG production. Comprehensive lupus-like phenotypes were evaluated. Single-cell RNA sequencing (scRNA-seq) was performed to characterize IFNγ-associated cellular and molecular pathways. IMQ treatment increased IFNγ-producing CD4+ T cells, along with Tfh cells, Tph cells, age-associated B cells, and plasma cells in WT mice. CD4+ T cells from IMQ-treated WT mice promoted B-cell differentiation and IgG production in co-culture assays. In IFNγ-/- mice, lupus-like phenotypes were significantly attenuated, and co-cultured B cells showed reduced differentiation and IgG production. Single-cell RNA sequencing revealed that IFNγ plays a critical role in promoting B cell differentiation and autoantibody production. IFNγ derived from activated CD4+ T cells plays a critical role in driving B-cell differentiation and promoting autoantibody production in IMQ-induced lupus.