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
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins c-akt