Unequal contribution of Akt isoforms in the double-negative to double-positive thymocyte transition.
Pre-TCR signals regulate the transition of the double-negative (DN) 3 thymocytes to the DN4, and subsequently to the double-positive (DP) stage. In this study, we show that pre-TCR signals activate Akt and that pharmacological inhibition of the PI3K/Akt pathway, or combined ablation of Akt1 and Akt2, and to a lesser extent Akt1 and Akt3, interfere with the differentiation of DN3 and the accumulation of DP thymocytes. Combined ablation of Akt1 and Akt2 inhibits the proliferation of DN4 cells, while combined ablation of all Akt isoforms also inhibits the survival of all the DN thymocytes. Finally, the combined ablation of Akt1 and Akt2 inhibits the survival of DP thymocytes. Constitutively active Lck-Akt1 transgenes had the opposite effects. We conclude that, following their activation by pre-TCR signals, Akt1, Akt2, and, to a lesser extent, Akt3 promote the transition of DN thymocytes to the DP stage, in part by enhancing the proliferation and survival of cells undergoing beta-selection. Akt1 and Akt2 also contribute to the differentiation process by promoting the survival of the DP thymocytes.
Mao
Changchuin
C
Molecular Oncology Research Institute, Tufts-New England Medical Center, 750 Washington Street, Boston, MA 02111, USA.
Tili
Esmerina G
EG
Dose
Marei
M
Haks
Mariëlle C
MC
Bear
Susan E
SE
Maroulakou
Ioanna
I
Horie
Kyoji
K
Gaitanaris
George A
GA
Fidanza
Vincenzo
V
Ludwig
Thomas
T
Wiest
David L
DL
Gounari
Fotini
F
Tsichlis
Philip N
PN
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D015870:Gene Expression; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D019076:Transgenes
D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt; D011948:Receptors, Antigen, T-Cell