Essential role of PI3Kdelta and PI3Kgamma in thymocyte survival.
Class 1 phosphoinositide 3-kinases (PI3Ks), consisting of PI3Kalpha, beta, gamma, and delta, are a family of intracellular signaling molecules that play important roles in cell-mediated immune responses. In thymocytes, however, their role is less clear, although PI3Kgamma is postulated to partially contribute to pre-TCR-dependent differentiation. We now report that PI3Kdelta, in conjunction with PI3Kgamma, is required for thymocyte survival and ultimately for T-cell production. Surprisingly, genetic deletion of the p110delta and p110gamma catalytic subunits resulted in a dramatic reduction in thymus size, cellularity, and lack of corticomedullary differentiation. Total thymocyte counts in these animals were 27-fold lower than in wild-type (WT) controls because of a diminished number of CD4+ CD8+ double-positive (DP) cells and were associated with T-cell depletion in blood and in secondary lymphoid organs. Moreover, this alteration in the DP population was intrinsic to thymocytes, because the reconstitution of p110gammadelta-/- animals with WT fetal liver cells restored the proportions of all thymocyte populations to those in WT controls. The observed defects were related to massive apoptosis in the DP population; TCRB expression, pre-TCR selection, and generation of DP cells appeared relatively unperturbed. Thus, class 1 PI3Ks work in concert to protect developing thymocytes from apoptosis.
Swat
Wojciech
W
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
Montgrain
Vivianne
V
Doggett
Teresa A
TA
Douangpanya
Jason
J
Puri
Kamal
K
Vermi
William
W
Diacovo
Thomas G
TG
D000818:Animals; D017209:Apoptosis; D020013:Calcium Signaling; D020134:Catalytic Domain; D002470:Cell Survival; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004622:Embryo, Mammalian; D007527:Isoenzymes / Q000172:deficiency / Q000502:physiology; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000502:physiology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology* / Q000201:enzymology* / Q000254:growth & development
D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C421683:Pik3cd protein, mouse; C546764:Pik3cg protein, mouse