Ndrg3 is a critical regulator of peripheral T cell maturation and homeostasis.

To provide protection, anticipatory T cell-dependent immunity is reliant on the generation and maintenance of a naïve T cell repertoire, which is sufficiently diverse to ensure recognition of newly encountered antigens. Therefore, under steady-state conditions, a given individual needs to maintain a large pool of naïve T cells, ready to respond to potential threats. Here, we demonstrate that N-myc downstream-regulated gene 3 (Ndrg3) is essential for naïve T cell stability. Mice with T cell-specific Ndrg3 loss are lymphopenic, with reduced numbers of conventional T cells and natural killer T cells. We show that in the absence of Ndrg3, naïve CD8+ T cells exhibit high rates of both proliferation and apoptosis, phenotypes that could be partially rescued by transgenic expression of a high-avidity T cell receptor. Furthermore, Ndrg3-deficient cells were refractory to interleukin-4, resulting in reduced Eomes induction, and a decreased virtual memory population. Our study therefore identifies Ndrg3 as an unexpected, pleiotropic regulator of T cell homeostasis.