Agonistic anti-4-1BB antibody promotes the expansion of natural regulatory T cells while maintaining Foxp3 expression

Scand J Immunol. 2007 Oct;66(4):435-40. doi: 10.1111/j.1365-3083.2007.01994.x.


The engagement of the 4-1BB (CD137) co-stimulatory pathway promotes the activation and proliferation of conventional CD4(+) T and CD8(+) T cells, but the role of 4-1BB co-stimulation in CD4(+) CD25(+) regulatory T cells (Treg) is less clear. In particular, whether 4-1BB stimulation affects the expression of Foxp3, a master gene for Treg, is unknown. This study demonstrates that co-stimulation of 4-1BB engaged by an agonistic antibody promotes the proliferation of Treg in a dependent manner of low-concentration interleukin-2 in vitro. The 4-1BB-expanded Treg maintain Foxp3 expression and their ability to suppress conventional CD4(+) T cells and their feature to produce no interleukin-2. However, the 4-1BB-expanded Treg produce increased levels of interferon-gamma, whose significance is unknown. Thus, 4-1BB co-stimulation plays a role in the expansion of functional CD4(+) CD25(+) Treg cells without adversely affecting their suppressive activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Coculture Techniques
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Forkhead Transcription Factors / biosynthesis*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Interferon-gamma / immunology
  • Interleukin-2 / immunology
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Lymphocyte Activation / drug effects
  • Mice
  • Mice, Inbred BALB C
  • RNA / chemistry
  • RNA / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Specific Pathogen-Free Organisms
  • T-Lymphocytes, Regulatory / immunology*
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / agonists
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology*


  • Antibodies, Monoclonal
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • RNA
  • Interferon-gamma