Targeting inducible costimulator expressed on CXCR5⁺PD-1⁺ T_H cells suppresses the progression of pemphigus vulgaris

Background: Pemphigus vulgaris (PV) is an autoimmune bullous disease mediated by autoantibodies against desmoglein 3 (DSG3). Inducible costimulator (ICOS) is a costimulatory receptor expressed on T cells and influences the activity of T follicular helper (T_FH) cells in various autoimmune diseases, but the roles of ICOS and T_FH cells in PV remain unclear. Objective: We examined the immunological characteristics, antigen specificity, and pathogenicity of CD4⁺ T-cell subpopulations, as well as the therapeutic effect of anti-ICOS blocking antibodies in PV. Methods: A mouse model of PV was established by adoptive transfer of immune cells from the skin-draining lymph nodes or spleens of DSG3-expressing skin-grafted Dsg3^–/– mice into Rag1^–/– mice. The T_FH cells and CD4⁺ T cells in PBMCs from PV patients were examined by flow cytometry. Results: Among CD4⁺ T cells from the mouse model, ICOS-positive T_FH cells were associated with B-cell differentiation and were required for disease induction. Using an MHC class II tetramer, DSG3-specific ICOS⁺ T_FH cells were found to be associated with anti-DSG3 antibody production and expanded in the absence of B cells. In human PV, the frequency of ICOS⁺CXCR5⁺PD-1⁺ memory CD4⁺ T cells correlated with the autoantibody level. Treatment with anti-ICOS blocking antibodies targeting ICOS⁺ T_FH cells decreased the anti-DSG3 antibody level and delayed disease progression in vivo. Conclusions: Mouse Dsg3-specific ICOS⁺ T_FH cells and human ICOS⁺CXCR5⁺PD-1⁺ T_H cells are associated with the anti-DSG3 antibody response in PV. ICOS expressed on CXCR5⁺PD-1⁺ T_H cells may be a therapeutic target for PV.