Phosphatidylinositol 3-Kinase Regulates Thymic Exit

Abstract

To understand the role of PI3K during T cell development, we generated transgenic mice expressing the N terminus of the PI3K catalytic subunit (p110ABD; ABD, adaptor binding domain) in thymocytes. Expression of p110ABD activates endogenous p110 and results in the accumulation of mature single-positive CD3highheat-stable Aglow thymocytes. This is mostly due to a defect in emigration of those cells, as shown by the delayed appearance of peripheral T cells in neonatal transgenic mice and by competitive adoptive transfer experiments. Although the mechanisms underlying these effects of PI3K are not yet clear, our results show an important role for PI3K activity in the regulation of mature thymocyte exit to the periphery.

Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes

“…5 B; Sinclair et al, 2008). This accumulation of mature SP cells has also been seen in thymocytes that express constitutively active PI3K (Barbee and Alberola-Ila, 2005) and reflects the observation that constitutive activation of PI3K promotes retention of mature T cells in the thymus. Importantly, deletion of PDK1 prevented the accumulation of CD24 low mature SP T cells in the thymus (Fig.…”

Signal integration and crosstalk during thymocyte migration and emigration

“…This results in upregulation of FOXO1 activity and increased KLF2 and S1P 1 transcription, thereby priming cells for thymic export (Figure 2). Indirect support for this model is that transgenic expression of constitutively active PI3K 95 , inactivation of the PI3K inhibitor PTEN (phosphatase and tensin homologue) 96 and antigen-mediated activation of mature thymocytes block thymocyte export 97 . Interestingly, in addition to S1P 1 , FOXO1 has also been shown to regulate the expression of CD62L and CCR7 89 perhaps through its regulation of KLF2 88 .…”

Human T-Cell Development and Thymic Egress: An Infectious Disease Perspective

“…CXCL12, also known as stromal-derived factor 1 (SDF-1), is a potent lymphocyte chemoattractant known to retain thymocytes at the corticomedullary junction, 33 the region of the thymus microenvironment at which thymocytes enter and exit the thymus until the cells are “told” to leave. 34 Additional factors such as the early growth response gene ( Egr1 , a transcriptional regulator involved in differentiation and mitogenesis), 35 integrin α5β1 (a mediator of migration and proliferation), 36,37 aryl hydrocarbon receptor (AHR, a helix-loop-helix transcription factor), 38,39 laminin-5 (a mediator of migration, organization, and attachment in tissues), 40 CCR7 (a mediator of migration from the cortex to the medulla during selection), 14,41,42 KLF2 (see above), 27 PI3 kinase (PI3K, a negative regulator of KLF2), 43 and phosphatase and tensin homolog (PTEN, a regulator of PI3K) 44 also bear mentioning because they have been shown to have roles in the process of egress (although much of the research is murine work). According to “textbook knowledge,” this maturation process takes ~2 weeks.…”