Biphasic role of 4-1BB in the regulation of mouse cytomegalovirus-specific CD8(+) T cells

Eur J Immunol. 2010 Oct;40(10):2762-8. doi: 10.1002/eji.200940256.


The initial requirement for the emergence of CMV-specific CD8(+) T cells is poorly understood. Mice deficient in the cosignaling TNF superfamily member, 4-1BB, surprisingly developed exaggerated early CD8(+) T-cell responses to mouse CMV (MCMV). CD8(+) T cells directed against acute MCMV epitopes were enhanced, demonstrating that 4-1BB naturally antagonizes these primary populations. Paradoxically, 4-1BB-deficient mice displayed reduced accumulation of memory CD8(+) T cells that expand during chronic/latent infection. Importantly, the canonical TNF-related ligand, 4-1BBL, promoted the accumulation of these memory CD8(+) T cells, whereas suppression of acute CD8(+) T cells was independent of 4-1BBL. These data highlight the dual nature of the 4-1BB/4-1BBL system in mediating both stimulatory and inhibitory cosignaling activities during the generation of anti-MCMV immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-1BB Ligand / immunology*
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • DNA, Viral / chemistry
  • DNA, Viral / genetics
  • Herpesviridae Infections / immunology*
  • Herpesviridae Infections / virology
  • Immunologic Memory / immunology
  • Interferon-gamma / blood
  • Lung / immunology
  • Lung / virology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muromegalovirus / immunology*
  • Polymerase Chain Reaction
  • Spleen / immunology
  • Spleen / virology
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / antagonists & inhibitors
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology*
  • Viral Envelope Proteins / chemistry
  • Viral Envelope Proteins / genetics


  • 4-1BB Ligand
  • DNA, Viral
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Viral Envelope Proteins
  • glycoprotein B, Simplexvirus
  • Interferon-gamma