Phosphatidylinositol 3-Kinase Regulates the CD4/CD8 T Cell Differentiation Ratio

Abstract

The signaling pathways that control T cell differentiation have only begun to be elucidated. Using T cell lines, it has been shown that class IA phosphatidylinositol 3-kinase (PI3K), a heterodimer composed of a p85 regulatory and a p110 catalytic subunit, is activated after TCR stimulation. Nonetheless, the contribution of p85/p110 PI3K isoforms in T cell development has not been described. Mice deficient in the other family of class I PI3K, p110γ, which is regulated by G protein-coupled receptors, exhibit reduced thymus size. Here we examine T cell development in p110γ-deficient mice and in mice expressing an activating mutation of the p85 regulatory subunit, p65PI3K, in T cells. We show that p110γ-deficient mice have a partial defect in pre-TCR-dependent differentiation, which is restored after expression of the p65PI3K activating mutation. Genetic alteration of both PI3K isoforms also affects positive selection; p110γ deletion decreased and p65PI3K expression augmented the CD4+/CD8+ differentiation ratio. Finally, data are presented showing that both PI3K isoforms influenced mature thymocyte migration to the periphery. These observations underscore the contribution of PI3K in T cell development, as well as its implication in determining the CD4+/CD8+ T cell differentiation ratio in vivo.

Phosphatidylinositol 3-Kinase Regulates Thymic Exit

“…Expression of a dominant negative form of p85 (⌬p85) in fetal thymic organ culture inhibited IL-7R-mediated proliferation and/or survival of thymocyte precursors without altering thymocyte differentiation, as assessed by the percentages of double-negative (DN), double-positive (DP), and single-positive (SP) thymocytes (12). In contrast, effects on the CD4/CD8 differentiation ratio have been reported in neonate p110␥ Ϫ/Ϫ animals and transgenic mice expressing the mildly activating class I A p65 PI3K transgene (13). Roles for both types of class I PI3Ks in thymocyte emigration are indicated by the observations that CD4 T cell appearance in the periphery (as assessed by thymic FITC or BrdU labeling) is potentiated by expression of the p65 PI3K transgene and that CD4 and CD8 thymocyte exits are inhibited by p110␥ deficiency (13).…”

“…In contrast, effects on the CD4/CD8 differentiation ratio have been reported in neonate p110␥ Ϫ/Ϫ animals and transgenic mice expressing the mildly activating class I A p65 PI3K transgene (13). Roles for both types of class I PI3Ks in thymocyte emigration are indicated by the observations that CD4 T cell appearance in the periphery (as assessed by thymic FITC or BrdU labeling) is potentiated by expression of the p65 PI3K transgene and that CD4 and CD8 thymocyte exits are inhibited by p110␥ deficiency (13). We thus sought to further delineate the role of class I A PI3K in thymocyte egress.…”

Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β

“…Most of the previous work on PI3Ks in lymphocyte activation have focused on the class I PI3Ks (p110 α, β, γ, and δ), which are responsible for the acute rise in PI(3,4,5)P 3 following antigen-receptor activation (5,6). Studies in knockout mice have demonstrated that p110δ and p110γ play partly redundant functions in T-cell activation, and are most important for T-cell receptor (TCR) signaling by peripheral T cells, as well as for T-cell development and survival (7)(8)(9)(10)(11). Although the exact role for PI(3,4,5)P 3 in T-cell activation is still controversial, recruitment and activation of a number of plekstrin-homology containing proteins by PI(3,4,5)P 3 is critical.…”

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

“…Interestingly, it was shown that introduction of a constitutively active mutant of class IA PI3K was able to restore the defect of p110␥ Ϫ/Ϫ mice (28). Rodríguez-Borlado et al (28) have reported that forced expression of a mutant form of p85␣ leading to activation of catalytic subunits resulted in acceleration of CD4 SP cell differentiation without affecting CD8 SP cells. In contrast, tg mice established by Barbee and Alberola-Ila (12) that express a portion of p110␣ subunit that lacks catalytic activity but binds p85␣, leading to activation of the endogenous catalytic subunit showed no difference in CD4/CD8 commitment.…”