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

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 CD4(-)CD8(-) (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 beta-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.

Figure 1

Thymocyte profiles of Akt1^−/−Akt2^−/− chimeras retrovirally transduced with Bcl-xL. Akt1^−/−Akt2^−/− fetal liver cells were retrovirally transduced with Bcl-xL or vector alone and injected into lethally irradiated congenic recipient mice. Thymuses were harvested 8 weeks post-transplant and analyzed for surface expression of CD4, CD8, CD25, c-kit, and lineage markers. Upper panels are gated on lineage negative thymocytes, lower panels are gated on CD4⁻,CD8⁻, lineage⁻ thymocytes. Lineage markers included NK1.1, CD11b, GR-1, CD11c, B220, and Ter119.