ICOS regulates the generation and function of human CD4+ Treg in a CTLA-4 dependent manner

PLoS One. 2013 Dec 2;8(12):e82203. doi: 10.1371/journal.pone.0082203. eCollection 2013.

Abstract

Inducible co-stimulator (ICOS) is a member of CD28/Cytotoxic T-lymphocyte Antigen-4 (CTLA-4) family and broadly expressed in activated CD4(+) T cells and induced regulatory CD4(+) T cells (CD4(+) iTreg). ICOS-related signal pathway could be activated by the interaction between ICOS and its ligand (ICOSL). In our previous work, we established a cost-effective system to generate a novel human allo-antigen specific CD4(hi) Treg by co-culturing their naïve precursors with allogeneic CD40-activated B cells in vitro. Here we investigate the role of ICOS in the generation and function of CD4(hi) Treg by interrupting ICOS-ICOSL interaction with ICOS-Ig. It is found that blockade of ICOS-ICOSL interaction impairs the induction and expansion of CD4(hi) Treg induced by allogeneic CD40-activated B cells. More importantly, CD4(hi) Treg induced with the addition of ICOS-Ig exhibits decreased suppressive capacity on alloantigen-specific responses. Dysfunction of CD4(hi) Treg induced with ICOS-Ig is accompanied with its decreased exocytosis and surface CTLA-4 expression. Through inhibiting endocytosis with E64 and pepstatin A, surface CTLA-4 expression and suppressive functions of induced CD4(hi) Treg could be partly reversed. Conclusively, our results demonstrate the beneficial role of ICOS-ICOSL signal pathway in the generation and function of CD4(hi) Treg and uncover a novel relationship between ICOS and CTLA-4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / metabolism*
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / metabolism*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Flow Cytometry
  • Humans
  • Inducible T-Cell Co-Stimulator Ligand / genetics
  • Inducible T-Cell Co-Stimulator Ligand / metabolism
  • Inducible T-Cell Co-Stimulator Protein / antagonists & inhibitors
  • Inducible T-Cell Co-Stimulator Protein / genetics
  • Inducible T-Cell Co-Stimulator Protein / metabolism*
  • Mice
  • NIH 3T3 Cells
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / pharmacology
  • T-Lymphocytes, Regulatory / metabolism*

Substances

  • CTLA-4 Antigen
  • ICOSLG protein, human
  • Inducible T-Cell Co-Stimulator Ligand
  • Inducible T-Cell Co-Stimulator Protein
  • Recombinant Fusion Proteins

Grants and funding

This work was supported in part by NSFC/RGC Joint Research Scheme (N_HKU 747/11), http://www.ugc.edu.hk/eng/rgc/fund/nsfc_rgc_jrs.htm; the Area of Excellence program supported by the University Grants Committee of the Hong Kong Special Administrative Region, China (AoE/M-12/06), http://www.ugc.edu.hk/eng/ugc/activity/aoes/aoes.htm. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.