Neural-tube defects such as anencephaly and spina bifida constitute a group of common congenital malformations caused by complex genetic and environmental factors. We have identified three mutations in the VANGL1 gene in patients with familial types (V239I and R274Q) and a sporadic type (M328T) of the disease, including a spontaneous mutation (V239I) appearing in a familial setting. In a protein-protein interaction assay V239I abolished interaction of VANGL1 protein with its binding partners, disheveled-1, -2, and -3. These findings implicate VANGL1 as a risk factor in human neural-tube defects.

BackgroundThe identification of the signals that should be provided by antigen-presenting cells (APCs) to induce a CD8+ T cell response in vivo is essential to improve vaccination strategies using antigen-loaded APCs. Although dendritic cells have been extensively studied, the ability of other APC types, such as B cells, to induce a CD8+ T cell response have not been thoroughly evaluated.Methodology/Principal FindingsIn this manuscript, we have characterized the ability of CD40-activated B cells, stimulated or not with Toll-like receptor (TLR) agonists (CpG or lipopolysaccharide) to induce the response of mouse naïve CD8+ T cells in vivo. Our results show that CD40-activated B cells can directly present antigen to naïve CD8+ T cells to induce the generation of potent effectors able to secrete cytokines, kill target cells and control a Listeria monocytogenes infection. However, CD40-activated B cell immunization did not lead to the proper formation of CD8+ memory T cells and further maturation of CD40-activated B cells with TLR agonists did not promote the development of CD8+ memory T cells. Our results also suggest that inefficient generation of CD8+ memory T cells with CD40-activated B cell immunization is a consequence of reduced Bcl-6 expression by effectors and enhanced contraction of the CD8+ T cell response.ConclusionsUnderstanding why CD40-activated B cell immunization is defective for the generation of memory T cells and gaining new insights about signals that should be provided by APCs are key steps before translating the use of CD40-B cell for therapeutic vaccination.

Programmed cell death 1 (PD-1) is an inhibitory receptor involved in T-cell activation, tolerance and exhaustion. Little is known on how the expression of PD-1 is controlled during T-cell activation. Recent studies demonstrated that NFATc1 and IRF9 regulate Pdcd1 (PD-1) transcription and that T-bet acts as a transcriptional repressor. In this study, we have investigated the role of the Notch signaling pathway in PD-1 regulation. Using specific inhibitors of the Notch signaling pathway, we showed decreased PD-1 expression and inhibition of Pdcd1 transcription by activated CD8(+) T cells. Chromatin immunoprecipitation further showed occupancy of the Pdcd1 promoter with RBPJk and Notch1 intracellular domain at RBPJk-binding sites. Our results identify the Notch signaling pathway as an important regulator of PD-1 expression by activated CD8(+) T cells.