Cell-intrinsic transforming growth factor-beta signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo

Immunity. 2009 Jul 17;31(1):145-57. doi: 10.1016/j.immuni.2009.06.015.


Although deficient CD8(+) T cell responses have long been associated with chronic viral infections, the underlying mechanisms are still unclear. Here we report that sustained transforming growth factor-beta (TGF-beta) expression and phosphorylation of its signaling mediator, Smad-2, were distinctive features of virus-specific CD8(+) T cells during chronic versus acute viral infections in vivo. The result was TGF-beta-dependent apoptosis of virus-specific CD8(+) T cells that related to upregulation of the proapoptotic protein Bim during chronic infection. Moreover, selective attenuation of TGF-beta signaling in T cells increased the numbers and multiple functions of antiviral CD8(+) T cells and enabled rapid eradication of the persistence-prone virus and memory generation. Finally, we found that cell-intrinsic TGF-beta signaling was responsible for virus-specific-CD8(+) T cell apoptosis and decreased numbers but was not necessary for their functional exhaustion. Our findings reveal persisting TGF-beta-Smad signaling as a hallmark and key regulator of CD8(+) T cell responses during chronic viral infections in vivo.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Animals
  • Apoptosis / immunology
  • Apoptosis Regulatory Proteins / immunology*
  • Apoptosis Regulatory Proteins / metabolism
  • Arenaviridae Infections / immunology*
  • Arenaviridae Infections / virology
  • Bcl-2-Like Protein 11
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Lymphocyte Depletion
  • Lymphocytic choriomeningitis virus / immunology
  • Membrane Proteins / immunology*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation / immunology
  • Proto-Oncogene Proteins / immunology*
  • Proto-Oncogene Proteins / metabolism
  • Signal Transduction / immunology
  • Smad2 Protein / immunology*
  • Smad2 Protein / metabolism
  • Transforming Growth Factor beta / immunology*
  • Transforming Growth Factor beta / metabolism


  • Apoptosis Regulatory Proteins
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Smad2 Protein
  • Smad2 protein, mouse
  • Transforming Growth Factor beta