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

A. Reum Kim, Dawoon Han, Ji Young Choi, Joon Seok, Song Ee Kim, Seong Hoon Seo, Hayato Takahashi, Masayuki Amagai, Su Hyung Park, Soo Chan Kim, Eui Cheol Shin, Jong Hoon Kim

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
DOIs
Publication statusAccepted/In press - 2020

Keywords

  • T follicular helper cell
  • desmoglein
  • humoral immunity
  • inducible costimulator
  • pemphigus vulgaris

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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