Akt1 and Akt2 are required for ¿ß thymocyte survival and differentiation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 29; p. 12105
• Main Authors: Juntilla, Marisa M, Wofford, Jessica A, Birnbaum, Morris J, Rathmell, Jeffrey C, Koretzky, Gary A
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 17.07.2007
• Subjects: Apoptosis; Cell growth; Cells; Immunology; Metabolism; Rodents
• ISSN: 0027-8424; 1091-6490

The β-selection checkpoint in αβT lymphocyte development occurs at the double negative (DN) 3 (...) stage, when further differentiation requires a signal from the newly rearranged TCRβ chain. Thymocytes with mutations in key signaling molecules in the phosphatidylinositol 3-kinase-Akt pathway manifest defects in survival, proliferation, and differentiation past the β-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 ... 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 ... 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 β-selection checkpoint. (ProQuest-CSA LLC: ... denotes formulae/symbols omitted.)