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Comment
. 2014 Jul;11(4):320-2.
doi: 10.1038/cmi.2014.11. Epub 2014 Mar 3.

Do PI3-kinase mutations drive T cells insane?

David Vermijlen  1 , Michel Y Braun  2 , Arnaud Marchant  2
Affiliations
Comment

Do PI3-kinase mutations drive T cells insane?

David Vermijlen et al. Cell Mol Immunol. 2014 Jul.
No abstract available

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Figures

Figure 1
Figure 1
Overview of PI3K/Akt/mTORC1/FOXO1 signaling pathways and consequences of PIK3CD mutations in CD8 T cells. Upon binding to their ligands, signaling via TCR/CD8, CD28 and/or cytokine receptors results in the activation of PI3K. At the plasma membrane, activated PI3K, composed of the catalytic subunit p110δ in T cells and of the regulatory subunit p85, phosphorylate PIP2 towards PIP3. PIP3 recruits pleckstrin homology-containing proteins such as AKT (also known as protein kinase B) and PDK1. Full activation of Akt requires phosphorylation by PDK1 and mTORC2. In the cytosol, Akt can activate mTORC1 by phosphorylating mTORC inhibitors. Akt goes also to the nucleus and triggers the nuclear exclusion of FOXO1 transcription factors that are important for cell quiescence and apoptosis. FOXO1 drives the transcription of eomes, IL-7R and the transcription factor KLF2. In turn, KLF2 drives the transcription of CCR7, CD62L and S1P1, thus regulating the trafficking of CD8 T cells. T cells from PASLI/APDS patients showed increased levels of PIP3, increased phosphorylation of Akt, increased degradation of FOXO1 (target of Akt) and increased phosphorylation of mTORC1 target genes (red arrows). The red arrows also indicate the possible consequences of these alterations on CD8 T-cell development and function such as effects on effector vs. memory formation and effects on survival and trafficking. APDS, activated PI3K-δ syndrome; FOXO1, forkhead box protein O1; KLF2, Krüppel-like Factor 2; mTORC1, mammalian target of rapamycin complex 1; PASLI, p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency; PDK1, phosphoinositide-dependent protein kinase; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; S1P1, sphingosine-1-phosphate receptor 1.
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References

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