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

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.

• Authors: 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
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 146 Issue 5 Pg. 1070-1079.e8 (11 2020) ISSN: 1097-6825 [Electronic] United States
• PMID: 32311391 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Antibodies, Blocking
• Autoantibodies
• CXCR5 protein, mouse
• Desmoglein 3
• Dsg3 protein, mouse
• Icos protein, mouse
• Inducible T-Cell Co-Stimulator Protein
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Receptors, CXCR5

Topics

• Animals
• Anti-Inflammatory Agents (therapeutic use)
• Antibodies, Blocking (therapeutic use)
• Autoantibodies (metabolism)
• Desmoglein 3 (genetics, metabolism)
• Disease Models, Animal
• Disease Progression
• Flow Cytometry
• Germinal Center (immunology)
• Humans
• Immunologic Memory
• Inducible T-Cell Co-Stimulator Protein (immunology, metabolism)
• Mice
• Mice, Knockout
• Pemphigus (immunology, therapy)
• Programmed Cell Death 1 Receptor (metabolism)
• Receptors, CXCR5 (metabolism)
• Th1 Cells (immunology, metabolism)