Dissecting the role of Phosphotidylinositol 3-Kinase (PI3K) δ in the germinal center reaction through a mouse model of hyperactivated Pik3cd

Abstract

Abstract The catalytic p110δ subunit of PI3K drives AKT pathways orchestrating activation and differentiation of T and B cells. Patients with gain of function mutations in Pik3cd (encoding for p110δ) exhibit a primary immunodeficiency characterized by lymphopenia, lymphadenopathy, recurrent and chronic infections, and occasionally lymphoma. They have reduced circulating naïve and increased effector T cell numbers, fewer class switched memory B cells and inefficient responses to vaccination. Nonetheless, in patient peripheral blood we find increased frequencies of T follicular helper (Tfh) cells. We have generated a mouse model expressing constitutively active p110δ that recapitulates many features of the human disease. Pik3cdMut mice, both in steady state condition and after immunization, display increased Tfh and germinal center (GC) B cell numbers in secondary lymphoid organs. Moreover, naïve mutant transgenic T cells (OT-II) preferentially acquire Tfh cell phenotype when adoptively transferred to WT mice, indicative of a T cell intrinsic defect. Nonetheless, despite increased Tfh and GC B cells, antigen specific B cell responses are reduced, particularly antigen-specific IgG. In contrast, we find the appearance of autoantibodies in Pik3cdMut mice. We further find that mutant OT-2 cells differentiate to Tfh cells independently from ICOS-ICOSL interactions. In line with this, mutant T cells show higher phosphorylation and inactivation of FoxO1, potent inhibitor of Tfh cell differentiation, that is phosphorylated and inhibited by AKT activation downstream of ICOS. Our results demonstrate that hyperactivated PI3Kδ leads to increased generation of Tfh cells and germinal centers, yet with defective in vivo function.