Sustained survivin expression from OX40 costimulatory signals drives T cell clonal expansion

Immunity. 2005 May;22(5):621-31. doi: 10.1016/j.immuni.2005.03.012.

Abstract

Sustained signaling from the T cell receptor (TCR) and costimulatory molecules is thought necessary for generating high numbers of effector T cells. Here, we show that Survivin is controlled in peripheral T cells by OX40 cosignaling via sustained PI3k and PKB activation. Survivin is induced by OX40 independent of mitotic progression in late G1, and blocking Survivin suppresses S-phase transition and division of T cells and leads to apoptosis. Moreover, Survivin expression alone is sufficient to restore proliferation and to antagonize apoptosis in costimulation-deficient T cells and can rescue T cell expansion in vivo. Survivin allows effector T cells to accumulate in large numbers, but Bcl-2 family proteins are required for T cell survival after the phase of active division. Thus, sustained Survivin expression from costimulatory signaling maintains T cell division over time and regulates the extent of clonal expansion.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Base Sequence
  • Cell Cycle
  • Cell Proliferation
  • DNA / genetics
  • In Vitro Techniques
  • Inhibitor of Apoptosis Proteins
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / immunology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Repressor Proteins
  • Signal Transduction
  • Survivin
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • Birc5 protein, mouse
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor
  • Repressor Proteins
  • Survivin
  • Tnfrsf4 protein, mouse
  • DNA
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt