Memory-phenotype CD8+ T cells can arise even in the absence of overt antigen stimulation. Virtual memory (VM) CD8+ T cells are CD8+ T cells that develop a memory phenotype in the periphery of WT mice in an IL-15-depedent manner. Innate CD8+ T cells, in contrast, are memory-phenotype CD8+ T cells which develop in the thymus in response to elevated thymic IL-4. It is not clear whether VM cells and innate CD8+ T cells represent two independent T cell lineages or whether they arise through similar processes. Here, we use mice deficient in Nedd4-family interacting protein 1 (Ndfip1) to show that overproduction of IL-4 in the periphery leads to an expanded VM population. Ndfip1−/− CD4+ T cells produce large amounts of IL-4 due to a defect in JunB degradation. This IL-4 induces a memory-like phenotype in peripheral CD8+ T cells that includes elevated expression of CD44, CD122 and Eomes, and decreased expression of CD49d. This is the first study to show that excess peripheral IL-4 is sufficient to cause an increase in the VM population. Our results suggest that VM and innate CD8+ T cells may be more similar than previously appreciated.

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants and the elderly. Despite its relatively low degree of antigenic variation, it causes frequent reinfection throughout life. Clinical manifestations of RSV disease and the immune response to infection differ in infants and the elderly, suggesting that vaccines designed to protect these two populations may require different attributes. Here, the authors describe the translational approach of utilizing data from epidemiology studies performed in these populations, the use of RSV diagnostics in clinical practice, lessons learned from previous vaccine clinical trials and the success of palivizumab in prevention of RSV disease in premature and high-risk infants to aid the development of safe and effective RSV vaccines.

The bacteria inhabiting the mammalian gastrointestinal (GI) tract play a vital role in normal digestion and immune function. In a healthy host, the immune system is tolerant to gut bacteria and does not mount an effector response to bacteria-derived antigens. Loss of tolerance to intestinal microflora has been associated with inflammatory bowel disease (IBD) in both mice and humans. Mice lacking Ndfip1, an adaptor protein for E3 ubiquitin ligases of the Nedd4-family, in T cells (Ndfip1-cKO) develop a disease resembling IBD. Inflammation in these mice is characterized by increased activation of peripheral T cells, infiltration of eosinophils into the GI tract, and epithelial hypertrophy in the esophagus. We hypothesized that this intestinal inflammation in Ndfip1-cKO mice is caused by a loss of T-cell tolerance to bacterial antigens. Here, we show that treatment of Ndfip1-cKO mice with broad-spectrum antibiotics drastically reduced bacterial load in stool but had little effect on T-cell activation and did not affect eosinophil infiltration into the GI tract or epithelial hypertrophy in the esophagus. Thus, inflammation in Ndfip1-cKO mice is not caused by a loss of tolerance to intestinal microbiota. Rather, T cell activation and eosinophilia may instead be triggered by other environmental antigens.

Nedd4-family interacting protein 1 (Ndfip1) is an adapter protein for Nedd4-family E3 ubiquitin ligases. Mice lacking Ndfip1 in both CD4+ and CD8+ T cells develop a severe atopic inflammatory disease at sites of environmental exposure and die prematurely. In part, this is because Ndfip1 expression in CD4+ T cells is needed to inhibit IL-4 production and permit differentiation into non-Th2 lineages. However, Ndfip1-/- mice that lack MHC Class II-restricted CD4+ T cells still develop inflammation at a young age. This suggests that Ndfip1 might also be important in CD8+ T cells. We show that Ndfip1-/- CD8+ T cells are more sensitive to TCR stimulation than WT cells. After activation, Ndfip1-/- CD8+ T cells produce more IFN-γ than their WT counterparts. Consistent with this, Ndfip1-/- CD8+ T cells have higher levels of Eomesodermin than control cells. Future studies will attempt to identify E3 ligases and substrates that regulate these CD8+ T cell functions.