CTLA4-Ig modifies dendritic cells from mice with collagen-induced arthritis to increase the CD4+CD25+Foxp3+ regulatory T cell population

J Autoimmun. 2010 Mar;34(2):111-20. doi: 10.1016/j.jaut.2009.07.006. Epub 2009 Aug 8.


Cytotoxic T lymphocyte antigen-4 (CTLA4) and IgG fusion protein, CTLA4-Ig, is a therapeutic agent used for rheumatoid arthritis. It binds B7 molecules on dendritic cells (DCs) and thereby blocks B7/CD28 costimulatory interaction and inhibits effective T cell proliferation. However, the effect of CTLA4-Ig on the regulatory T cell (Treg) is still not known. In this study, we investigated the influence of CTLA4-Ig on the CD4+CD25+Foxp3+ Treg population in collagen-induced arthritis (CIA) mouse model. CTLA4-Ig suppressed CIA and increased the CD4+CD25+Foxp3+ Treg population in joint and spleen. When CD11c + DCs and CD4+T cells from CIA mice were cultured with anti-CD3, CTLA4-Ig increased the CD4+CD25 + Foxp3+ Treg population in a TGF-beta-dependent manner. When CD11c + DCs from CIA mice were treated with CTLA4-Ig and adoptively transferred into CIA-induced mice, arthritis did not develop in association with the increase in CD4+CD25+Foxp3+ Treg population. However, in CTLA4-Ig-untreated DC-transferred CIA mice, arthritis developed and then rapidly progressed. Our study demonstrated that CTLA4-Ig suppressed CIA by modifying DCs from CIA mice into tolerogenic DCs to increase the CD4+CD25+Foxp3+ Treg population and this seems to be the new immune regulatory mechanism of CTLA4-Ig.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Adoptive Transfer
  • Animals
  • Arthritis, Experimental / immunology*
  • Arthritis, Experimental / therapy
  • CD4 Antigens / biosynthesis
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / immunology
  • Cytokines / metabolism
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism*
  • Dendritic Cells / pathology
  • Dendritic Cells / transplantation
  • Forkhead Transcription Factors / biosynthesis
  • Immunoconjugates / administration & dosage*
  • Interleukin-2 Receptor alpha Subunit / biosynthesis
  • Lymphocyte Activation / drug effects
  • Male
  • Mice
  • Mice, Inbred DBA
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocyte Subsets / pathology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / pathology


  • CD4 Antigens
  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Immunoconjugates
  • Interleukin-2 Receptor alpha Subunit
  • Abatacept