Defective inducible T cell costimulator signalling drives neuropilin-1hi CD4+ T cell-mediated non-germinal centre B cell activation via impaired regulatory T cell maintenance in a lupus model

Inducible T cell costimulator (ICOS) signalling is essential for follicular helper T (Tfh) cell activation and has emerged as a therapeutic target in B cell-dependent autoimmune diseases such as systemic lupus erythematosus (SLE). However, its dual role in supporting both Foxp3 + regulatory T (Treg) cells and Tfh cell responses complicates therapeutic interventions. Here, we demonstrate that disruption of ICOS signalling in Sanroque mice impairs Treg cell maintenance, unleashing pathogenic T cell responses. In ICOS ligand-deficient Sanroque mice, defective ICOS signalling disrupts canonical Tfh cell-dependent germinal centre (GC) responses but fails to prevent autoantibody production and reverse SLE-like symptoms. Notably, Treg cell reduction in ICOS ligand-deficient Sanroque mice is associated with augmentation of self-reactive neuropilin-1 (Nrp-1) hi CD4 + conventional T (Tconv) cells. Mechanistically, Nrp-1 hi CD4 + Tconv cells effectively produce IFN-γ and outcompete Treg cells for dendritic cell engagement. Nrp-1 hi CD4 + Tconv cells acquire PD-1 hi CXCR5 − peripheral helper T (Tph) cell phenotype, and drive non-GC B cell responses by promoting the induction of age-associated B cells through contact-dependent mechanisms in the absence of Treg cells. Our findings highlight that ICOS signalling orchestrates GC and non-GC B cell responses in SLE via impaired Treg cell maintenance, and also underscore potential risks in therapeutic strategies targeting ICOS signalling for SLE, as it could inadvertently promote T cell-mediated inflammation and non-GC B cell responses through the induction of age-associated B cells.