The p110δ Isoform of Phosphatidylinositol 3-Kinase Controls the Quality of Secondary Anti- Leishmania Immunity by Regulating Expansion and Effector Function of Memory T Cell Subsets

Abstract

We showed previously that mice with an inactivating knockin mutation in the p110δ isoform of PI3K (referred to as p110δD910A mice) displayed enhanced primary resistance to Leishmania major despite mounting paradoxically impaired T cell responses. In this study, we show that p110δD910A mice are impaired in their secondary (memory) anti-Leishmania responses in vitro and in vivo. Following secondary L. major challenge, p110δD910A mice exhibited reduced delayed-type hypersensitivity response and weaker parasite control compared to wild-type mice. Using adoptive transfer experiments, we show that immune T cells from healed p110δD910A mice were impaired in their proliferation and effector cytokine (IFN-γ) responses upon L. major challenge. Interestingly, Leishmania-reactive T cells from healed p110δD910A mice contain severalfold lower numbers of CD62Llo and CD62hi T cells than those from healed wild-type mice. The reduction in numbers of CD62Llo T cells in p110δD910A mice is due to failure of their CD62Lhi T cells to downregulate CD62L expression in response to L. major. Furthermore, although CD62Llo cells from p110δD910A mice could home efficiently to lymphoid organs, their ability to exit these tissues and emigrate to cutaneous sites of infection was greatly impaired. Collectively, our data identify PI3K signaling as important events that control memory T cell subset differentiation, generation, effector function, and recruitment to cutaneous tissues and suggest that manipulating this pathway could provide means of enhancing desired memory T cell subset, response during vaccination, or both.