4-1BB-dependent inhibition of immunosuppression by activated CD4+CD25+ T cells

J Leukoc Biol. 2004 May;75(5):785-91. doi: 10.1189/jlb.1003491. Epub 2003 Dec 23.

Abstract

4-1BB (CD137) is a costimulatory molecule involved in the activation and survival of CD4, CD8, and natural killer cells. Although a great deal has been learned as to how 4-1BB-mediated signaling governs the immunity of conventional T cells, the functional role of 4-1BB in the context of CD4(+)CD25(+) regulatory T cell (Tr) activation is largely unknown. Using 4-1BB-intact and -deficient mice, we investigated the effect of the 4-1BB/4-1BB ligand pathway on the suppressive function of Tr cells. Our data indicate that although 4-1BB is expressed on Tr cells, its contribution to their proliferation is minimal. We also showed that signaling through the 4-1BB receptor inhibited the suppressive function of Tr cells in vitro and in vivo. It is interesting that anti-4-1BB-mediated but not anti-GITR-directed inhibition was more potent when Tr cells were preactivated. Collectively, these data indicate that 4-1BB signaling is critical in Tr cell immunity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 4-1BB Ligand
  • Animals
  • Antigens, CD
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / transplantation
  • Female
  • Graft vs Host Disease / etiology
  • Immunity*
  • Lymphocyte Activation / immunology*
  • Lymphocyte Transfusion / adverse effects
  • Mice
  • Mice, Knockout
  • Receptors, Interleukin-2
  • Receptors, Nerve Growth Factor / deficiency
  • Receptors, Nerve Growth Factor / immunology
  • Receptors, Nerve Growth Factor / physiology*
  • Receptors, Tumor Necrosis Factor / deficiency
  • Receptors, Tumor Necrosis Factor / immunology
  • Receptors, Tumor Necrosis Factor / physiology*
  • Signal Transduction / immunology
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / transplantation
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • 4-1BB Ligand
  • Antigens, CD
  • Receptors, Interleukin-2
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf9 protein, mouse
  • Tnfsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Necrosis Factor-alpha