The p85α Regulatory Subunit of Class IA Phosphoinositide 3-Kinase Regulates β-Selection in Thymocyte Development

Abstract

We examined the role of class IA PI3K in pre-TCR controlled β-selection and TCR-controlled positive/negative selection in thymic development. Using mice deficient for p85α, a major regulatory subunit of the class IA PI3K family, the role of class IA PI3K in β-selection was examined by injection of anti-CD3ε mAb into p85α−/−Rag-2−/− mice, which mimics pre-TCR signals. Transition of CD4−CD8− double-negative (DN) to CD4+CD8+ double-positive (DP) thymocytes triggered by anti-CD3ε mAb was significantly impaired in p85α−/−Rag-2−/− compared with p85α+/−Rag-2−/− mice. Furthermore, DP cell numbers were lower in p85α−/−DO11.10/Rag-2−/− TCR-transgenic mice than in DO11.10/Rag-2−/− mice. In addition, inhibition by IC87114 of the major class IA PI3K catalytic subunit expressed in lymphocytes, p110δ, blocked transition of DN to DP cells in embryonic day 14.5 fetal thymic organ culture without affecting cell viability. In the absence of phosphatase and tensin homolog deleted on chromosome 10, where class IA PI3K signals would be amplified, the DN to DP transition was accelerated. In contrast, neither positive nor negative selection in Rag-2−/−TCR-transgenic mice was perturbed by the lack of p85α. These findings establish an important function of class IA PI3K in the pre-TCR-controlled developmental transition of DN to DP thymocytes.

Alternative Splicing Controlled by Heterogeneous Nuclear Ribonucleoprotein L Regulates Development, Proliferation, and Migration of Thymic Pre-T Cells

“…This is also consistent with the increased basal-activating phosphorylation of Lck at Y394 in hnRNP Ldeficient cells compared with wt controls. It is known that Lck mediates activation of T cells through recruitment and phosphorylation of its substrates, such as ZAP70, but also activates PI3K (42)(43)(44)(45). Hence, the higher basal Akt and ERK phosphorylation and related increased proliferation rate observed in hnRNP L-deficient DN4 cells are likely to be a consequence of the aberrant Lck signaling in these cells.…”

PI3Ks in Lymphocyte Signaling and Development

“…Strikingly, p110δ-p110γ double-deficient mice show a dramatic reduction in thymocyte numbers caused by a block at the DN3-DN4 stage of development in addition to reduced DP cell survival [60, 61]. Pre-TcR signaling as this stage was mostly controlled by p85α and p110δ [62]. The unexpected redundancy between p110δ and p110γ therefore suggested that GPCRs may play a greater role at this developmental stage than previously appreciated.…”

An overview of IL-7 biology and its use in immunotherapy

“…The PI3K is recruited to the membrane where it produces the phosphatidyl-inositol PIP3 by phosphorylating PIP2. PIP3 activates downstream genes with a plekstrin homology domain such as PDK1 and Akt (Shiroki et al, 2007). Akt, in turn, phosphorylates genes that regulate cell metabolism, cell cycle progression and survival, such as GSK3β, P27 and the death protein Bad.…”