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

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 ) cells in various autoimmune diseases, but the roles...

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Bibliographic Details
Published in:Journal of allergy and clinical immunology 2020-11, Vol.146 (5), p.1070
Main Authors: Kim, A Reum, Han, Dawoon, Choi, Ji Young, Seok, Joon, Kim, Song-Ee, Seo, Seong-Hoon, Takahashi, Hayato, Amagai, Masayuki, Park, Su-Hyung, Kim, Soo-Chan, Shin, Eui-Cheol, Kim, Jong Hoon
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Language:English
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Summary: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 ) cells in various autoimmune diseases, but the roles of ICOS and T cells in PV remain unclear. 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. 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 cells and CD4 T cells in PBMCs from PV patients were examined by flow cytometry. Among CD4 T cells from the mouse model, ICOS-positive T cells were associated with B-cell differentiation and were required for disease induction. Using an MHC class II tetramer, DSG3-specific ICOS T 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 cells decreased the anti-DSG3 antibody level and delayed disease progression in vivo. Mouse Dsg3-specific ICOS T cells and human ICOS CXCR5 PD-1 T cells are associated with the anti-DSG3 antibody response in PV. ICOS expressed on CXCR5 PD-1 T cells may be a therapeutic target for PV.
ISSN:1097-6825
DOI:10.1016/j.jaci.2020.03.036