The role of the PI3K-AKT kinase pathway in T-cell development beyond the β checkpoint

✍ Scribed by Ling Xue; Leslie Chiang; Chulho Kang; Astar Winoto

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 340 KB
• Volume: 38
• Category: Article
• ISSN: 0014-2980
• DOI: 10.1002/eji.200838614

✦ Synopsis

Abstract

The PI3K‐AKT pathway can mediate diverse biological responses and is crucial for optimal immune responses and lymphocyte development. Deletion of PI3K subunits or AKT leads to blockage of T‐cell development at the TCR‐β checkpoint. Studies with over‐expression of constitutively activated AKT have implicated this pathway in anti‐apoptosis of developing thymocytes and in development of regulatory T cells. However, the role of endogenous PI3K‐AKT in T‐cell development beyond the TCR‐β checkpoint remains unclear. Here, we inhibited the endogenous PI3K‐AKT pathway in thymocytes after double negative stages by expressing the negative regulator, PTEN. These mice exhibit normal early T‐cell development, but the transition from intermediate single positive to double positive (DP) thymocytes is inhibited, leading to a significantly decreased number of DP, single positive thymocytes and peripheral T cells. Proliferation of peripheral T cells is reduced but apoptosis of DP cells and subsequent T‐cell maturation, including regulatory T cells, are normal. AKT phosphorylation can be readily observed in most WT T‐cell compartments but not DP thymocytes in response to TCR activation. Thus, the PI3K‐AKT pathway is crucial for the transition of intermediate single positive to DP thymocytes but is dispensable for apoptosis and maturation of developing thymocytes.