Akt1 and Akt2 are required for αβ thymocyte survival and differentiation

Abstract

The ␤-selection checkpoint in ␣␤T lymphocyte development occurs at the double negative (DN) 3 (CD4 ؊ CD8 ؊ CD25 ؉ c-kit ؊ ) stage, when further differentiation requires a signal from the newly rearranged TCR ␤ chain. Thymocytes with mutations in key signaling molecules in the phosphatidylinositol 3-kinase-Akt pathway manifest defects in survival, proliferation, and differentiation past the ␤-selection checkpoint. However, little information is available regarding the role of Akt itself in thymocyte development. In this study, we explore the role of the two Akt isoforms most highly expressed in the thymus, Akt1 and Akt2, in early T cell development. Using several complementary approaches, we find that deletion of Akt1 results in only minor defects in thymocyte development. The Akt1 ؊/؊ Akt2 ؊/؊ thymocytes manifest a severe developmental block at the DN3 stage and ultimately fail to repopulate the T cell compartment of an irradiated host. Further, we show that Akt1 ؊/؊ Akt2 ؊/؊ DN3 cells have decreased glucose uptake and die in response to TCR stimulation in vitro. Study of thymocytes from the genetically altered mice suggests that the cause of the developmental defect is due to apoptosis, partially caused by decreased cellular growth and metabolism at the DN3 stage. Our results show that Akt protects thymocytes from cell death during the ␤-selection checkpoint.apoptosis ͉ metabolism ͉ thymic development

Differential regulation of CIDEA and CIDEC expression by insulin via Akt1/2- and JNK2-dependent pathways in human adipocytes

“…4 ). Consistent with our results, it has been reported that combined loss of Akt1/2 causes increased apoptosis after stimulation in thymocytes ( 20 ). Inhibition of Akt signaling induces apoptosis in 3T3-L1 adipocytes ( 48 ).…”

Increased numbers of thymic and peripheral CD4+ CD25+Foxp3+ cells in the absence of CD5 signaling

“…This result correlates with the increased susceptibility of CD4 1 Foxp3 À CD5 À/À thymocytes to apoptosis. In this context, Akt was shown to play a role in thymocyte survival [63,64], through the induction of Bcl-2 family members, such as Bcl-XL [65] and A1 [66].…”

“…This result correlates with the increased susceptibility of CD4 1 Foxp3 À CD5 À/À thymocytes to apoptosis. In this context, Akt was shown to play a role in thymocyte survival [63,64], through the induction of Bcl-2 family members, such as Bcl-XL [65] and A1 [66].In contrast to naïve thymocytes, the absence of CD5 did not affect Akt phosphorylation in Treg, in response to TCR crosslinking. Interestingly, Bensinger et al [67] recently showed that peripheral Treg, stimulated in the presence of IL-2, show increased survival in the absence of Akt phosphorylation, suggesting that Akt activation is dispensable for Treg survival.…”

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy

“…6,10,11 These joined signals activate the PI3K/AKT/mTOR-pathway that has been shown to play a pivotal role in regulating CD8 + T cell differentiation and memory formation. 12,13 Interestingly however, interference of PI3K/AKT signaling does not severely impair the proliferation of murine CD8 + T cells. 14 Therefore, we and others exploited pharmacological AKT-inhibition to generate early memory T SCM/CM -like CD8 + T cells for ex vivo adoptive cell therapy.…”