Abatacept (CTLA-4Ig) treatment reduces T cell apoptosis and regulatory T cell suppression in patients with rheumatoid arthritis

Rheumatology (Oxford). 2016 Apr;55(4):710-20. doi: 10.1093/rheumatology/kev403. Epub 2015 Dec 16.

Abstract

Objective: Abatacept (CTLA-4Ig) blocks CD28-mediated T cell activation by binding to the costimulatory B7 ligands CD80/CD86 on antigen presenting cells. Costimulatory molecules, however, can also be expressed on T cells upon activation. Therefore, the aim of our study was to investigate direct effects of CTLA-4Ig on distinct T cell subsets in RA patients.

Methods: Phenotypic and functional analyses of CD4(+) T cells, including CD4(+) FoxP3(+) CD25(+) regulatory T cells (Treg), from RA patients were performed before and during CTLA-4Ig therapy. In addition T cells from healthy volunteers were analysed on in vitro culture with CTLA-4Ig or anti-CD80 and anti-CD86 antibodies. Apoptotic DNA fragmentation in CD4(+) and CD4(+) FoxP3(+) T cells was measured by TUNEL staining.

Results: We observed an increase in T cells, including Treg cells, after initiation of CTLA-4Ig therapy, which was linked to a downregulation of activation-associated marker molecules and CD95 on CD4(+) T cells and Treg cells. CTLA-4Ig decreased CD95-mediated cell death in vitro in a dose-dependent manner. Functional analysis of isolated Treg cells from RA patients further revealed a diminished suppression of responder T cell proliferation. This was found to be due to CTLA-4Ig-mediated blocking of CD80 and CD86 on responder T cells that led to a diminished susceptibility for Treg cell suppression.

Conclusion: CTLA-4Ig therapy in RA patients exerts effects beyond the suppression of T cell activation, which has to be taken into account as an additional mechanism of CTLA-4Ig treatment.

Keywords: CTLA-4Ig; Foxp3; abatacept; regulatory T cells; rheumatoid arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept / pharmacology*
  • Abatacept / therapeutic use
  • Antirheumatic Agents / pharmacology*
  • Antirheumatic Agents / therapeutic use
  • Apoptosis / drug effects*
  • Apoptosis / immunology
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / immunology*
  • CD4-Positive T-Lymphocytes / drug effects
  • Cells, Cultured
  • Female
  • Humans
  • Immune Tolerance / drug effects
  • Immunophenotyping
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Male
  • Middle Aged
  • T-Lymphocyte Subsets / drug effects*
  • T-Lymphocytes, Regulatory / drug effects*
  • fas Receptor / immunology

Substances

  • Antirheumatic Agents
  • FAS protein, human
  • fas Receptor
  • Abatacept