Elsevier

Immunology Letters

Volume 116, Issue 2, 15 March 2008, Pages 104-110
Immunology Letters

Review
Critical roles of the PI3K/Akt signaling pathway in T cell development

https://doi.org/10.1016/j.imlet.2007.12.008Get rights and content

Abstract

Thymocyte development requires an integration of extracellular cues to enforce lineage commitment at multiple defined checkpoints in a stage-specific manner. Critical signals from the pre-TCR, Notch, and the receptor for interleukin-7 (IL-7) dictate cellular differentiation from the CD4CD8 (double negative) stage to the CD4+CD8+ (double positive) stage. The PI3K/Akt signaling pathway is required to translate these extracellular signaling events into multiple functional outcomes including cellular survival, proliferation, differentiation, and allelic exclusion at the β-selection checkpoint. However, a complete understanding of the contributions made by the PI3K/Akt pathway in thymocyte development has not been straightforward. This review highlights studies that support the model that the PI3K/Akt pathway is essential for thymocyte survival. We provide new evidence that Akt-mediated survival is not solely due to the increased expression of Bcl-xL but also is a consequence of the role played by Akt to support metabolism in proliferating thymocytes.

Section snippets

Early T cell development

Acquisition of a complete peripheral T cell repertoire requires that T cell progenitors undergo a series of tightly regulated developmental events that depend on integration of signaling cascades downstream of the pre-T cell receptor (TCR) and then the mature TCR. Creating a pool of mature T cells requires that developing thymocytes interpret signals from the extracellular environment in a spatial and temporal-specific manner [1]. The first step in T cell development is the emigration of early

PI3K and PDK1 are required for survival and proliferation at the β-selection checkpoint

Experimental evidence suggests that DN3 cell survival requires that signals delivered by multiple receptors, including Notch, the receptor for interleukin-7 (IL-7), and the pre-TCR, be appropriately integrated [14], [15], [16], [17]. However, it remains unclear which signaling pathway(s) is (are) most critical for survival during the transition from the DN3 to DP stage. One pathway common to all three receptors is the phosphatidylinositol 3-kinase (PI3K) signal transduction cascade. Activation

Akt is required to maintain thymocyte survival

Given the mounting evidence implicating the PI3K pathway in thymocyte development, several groups began to investigate the importance of Akt, a downstream effector of PI3K activation, in this process. Targeting Akt to the plasma membrane, either through the use of a myristoylation sequence or a gag sequence, bypasses the requirement for lipid accumulation at the plasma membrane and results in constitutive activation of Akt. Based on in vitro studies using the myristoylated Akt construct, it was

Do PI3K and Akt contribute to allelic exclusion?

In-frame rearrangements at the TCRβ loci and the subsequent signal from the pre-TCR dictate the fate of DN3 cells. An estimated four out of nine DN3 cells fail to produce a TCRβ chain and eventually die due to neglect [50]. The current model for allelic exclusion is that a signal from the pre-TCR negatively regulates V-DJ rearrangements at the TCRβ loci. In support of this model, PKCθ and Lck promote proliferation and differentiation but also enforce allelic exclusion at the TCRβ locus [51],

Conclusion

At the DN3-DP transition, the formation of the pre-TCR at the β-selection checkpoint triggers a proliferative burst, estimated to be about 10 cell divisions [58]. One model posits that highly proliferative cells become more susceptible to apoptosis to limit tissue expansion [59], [60]. In this model, parallel signals induce proliferation and apoptosis, ensuring that tissue size is homeostatically preserved. However, when there is a blockade of apoptosis, the tissue undergoes expansion, and in

Acknowledgement

This work was supported by NIH grants P01 CA93615 (G.A.K. and M.M.J.) and F31 A1056671 (M.M.J.).

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