Accumulating studies have identified self-DNA as driving IgG anti-double-stranded DNA (anti-dsDNA) in lupus, though the underpinning mechanisms of this process remain largely undefined. Here, we explored the activity of transcription factor retinoic acid receptor-related orphan nuclear receptor γt (RORγt) in the differentiation and function of self-DNA-specific follicular helper T (Tfh) cells in lupus.
B6, TCRα
Unlike normal self-DNA, immunogenic self-DNA and pathogen DNA efficiently induced IgG responses. Immunogenic self-DNA induced IgG in a CD4+ T cell-dependent manner, which was abrogated by RORγt deficiency. In contrast, RORγt was not required for the generation of pathogen DNA-induced IgG. Further analyses identified RORγt as essential for the differentiation and function of Tfh cells in response to immunogenic self-DNA, assigning IL-17 as a feature cytokine. These IL-17-positive Tfh cells functioned independent of inducible costimulator (ICOS), critically supporting IgG generation. Targeting immunogenic self-DNA-specific Tfh cells by RORγ knockdown and IL-17 blockade ameliorated IgG response and lupus nephritis in a humanized mouse model. The presence of IL-17-positive Tfh cells was associated with IgG anti-dsDNA levels and were expanded by circulating immunogenic self-DNA in lupus patients.
Immunogenic self-DNA instructs ICOS-dispensable IL-17-positive Tfh cells via RORγt to produce an IgG anti-dsDNA response. As such, IL-17-positive Tfh cells are a promising therapeutic target for lupus patients.