Sustained survivin expression from OX40 costimulatory signals drives T cell clonal expansion.
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.
Song
Jianxun
J
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
So
Takanori
T
Cheng
Mary
M
Tang
Xiaohong
X
Croft
Michael
M
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002453:Cell Cycle; D049109:Cell Proliferation; D004247:DNA / Q000235:genetics; D066298:In Vitro Techniques; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D012097:Repressor Proteins; D015398:Signal Transduction; D000077022:Survivin; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism
D004247:DNA; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D012097:Repressor Proteins; D000077022:Survivin; C117749:Birc5 protein, mouse; C505717:Tnfrsf4 protein, mouse