Recently, a novel human primary immunodeficiency caused by heterozygous gain-of-function (GOF) mutations in PIK3CD, which encodes the p110δ catalytic subunit of Phosphoinositide 3-kinase (PI3K), has been described. Symptoms commonly observed in patients with PIK3CD GOF mutations include recurrent respiratory infections, hepatosplenomegaly, lymphadenopathy, lymphopenia, increased IgM, reduced IgG2, altered T and B cell populations, defective vaccine responses and lymphoma. These symptoms suggest dysregulation of both T and B cells in these patients consistent with the activation of PI3K downstream of numerous lymphocyte cell surface molecules, including the T and B cell receptors, that control lymphocyte activation, differentiation and proliferation. In order to better dissect the cellular mechanisms underlying this condition we generated a mouse model of PI3K GOF utilizing CRISPR/Cas9 technology to introduce the E1021K mutation (the most commonly identified mutation in patients) into Pik3cd. Extensive flow cytometry phenotyping revealed that PI3K overactivation has a small effect on thymic development but a more striking effect on peripheral T cells with decreased numbers of naïve T cells and a concurrent increase in memory cells. Furthermore, the activation profile of the PI3K GOF mice also demonstrated an increased frequency of T follicular helper (Tfh) cells as well as an enlarged germinal centre (GC) formation. To elucidate the T cell intrinsic effects of the PI3K GOF, we generated mixed bone marrow chimeras as well as utilizing a model of adoptive transfer of antigen specific T cells. Together, these experiments revealed both T cell intrinsic and extrinsic components leading to the changes in T cells activation and differentiation in PI3K GOF mice, helping to explain the pathophysiology of these patients.