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 (TFH) cells in various autoimmune diseases, but the roles of ICOS and TFH 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 TFH 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 TFH cells were associated with B-cell differentiation and were required for disease induction. Using an MHC class II tetramer, DSG3-specific ICOS+ TFH 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+ TFH cells decreased the anti-DSG3 antibody level and delayed disease progression in vivo. Conclusions: Mouse Dsg3-specific ICOS+ TFH cells and human ICOS+CXCR5+PD-1+ TH cells are associated with the anti-DSG3 antibody response in PV. ICOS expressed on CXCR5+PD-1+ TH cells may be a therapeutic target for PV.
ASJC Scopus subject areas
- Immunology and Allergy