The functions of phosphatidylinositol 3-kinase in T lymphocyte development: Roles in positive selection and thymic exit

Phosphatidylinositol 3-kinase (PI3K) is an important regulator of cell survival, proliferation, activation, and migration in multiple organisms and cell types. We have sought to determine how PI3K may regulate T lymphocyte development, a process that entails exquisitely coordinated phases of proliferation, differentiation, and intra-organ movement. We have generated transgenic mice that express a PI3K gain-of-function mutant specifically in thymocytes. The p110ABD transgene constitutes the adaptor binding domain of the PI3K catalytic subunit and this fragment associates with adaptor subunits in vivo. p110ABD expression induces constitutive PI3K function, as assessed by the activity of the downstream effector Akt. Furthermore, p110ABD-induced PI3K function potentiates Ca++ influx induced by sub-optimal crosslinking of the antigen receptor (TCR) on immature thymocytes. Enhancing PI3K activity in developing T cells results in the specific accumulation of late-stage, mature HSAlo CD3hi thymocytes of both lineages. The increased numbers of mature thymocytes can be partly attributed to an improvement in positive selection. This is demonstrated by the ability of p110ABD to promote efficient positive selection of transgenic AND TCR thymocytes in a background that mediates sub-optimal differentiation. The improvement in selection is not biased to the CD4 lineage, since CD4 lineage development is not specifically improved in class I-restricted transgenic TCR animals expressing p110ABD. Furthermore, the effect is specific to positive selection since immature thymocyte survival and negative selection are unaffected by p110ABD expression. The increased mature populations are also partly the result of impaired thymocyte emigration. p110 ABD T cells colonize the periphery of neonatal animals and irradiated recipients slower than do non-transgenic T cells. The ability of PI3K to regulate positive selection effect is probably due to enhancement of Itk-mediated Ca ++ influx. By contrast, the role of PI3K in emigration appears to be independent of known chemotactic or adhesive factors and may instead reflect the importance of subcellular organization for chemokine receptor signaling.