Summary Streptococcus pneumoniae is a leading cause of mortality in young children. While successful conjugate polysaccharide vaccines exist, a less expensive serotype-independent protein-based pneumococcal vaccine offers a major advancement for preventing life-threatening pneumococcal infections, particularly in developing nations. IL-17A-secreting CD4+ T cells (TH17) mediate resistance to mucosal colonization by multiple pathogens including S. pneumoniae. Screening an expression library containing >96% of predicted pneumococcal proteins, we identified antigens recognized by TH17 cells from mice immune to pneumococcal colonization. The identified antigens also elicited IL-17A secretion from colonized mouse splenocytes and human PBMCs suggesting that similar responses are primed during natural exposure. Immunization of two mouse strains with identified antigens provided protection from pneumococcal colonization that was significantly diminished in animals treated with blocking CD4 or IL-17A antibodies. This work demonstrates the potential of proteomic screening approaches to identify specific antigens for the design of subunit vaccines against mucosal pathogens via harnessing TH17-mediated immunity.

Wiskott Aldrich syndrome (WAS) is caused by mutations in the WAS IntroductionWiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency caused by mutations of the WAS gene that is widely expressed within hematopoietic cells. 1 The clinical phenotype of WAS is characterized by congenital thrombocytopenia, combined immunodeficiency, and eczema. 1 The WAS protein (WASp) includes several functional domains that couple signal transduction to reorganization of the actin cytoskeleton. As a result, WASp has significant influence on processes such as cell adhesion, migration, assembly/turnover of cell surface receptors, and immunologic synapse formation. 1,2 Several studies in patients with WAS and in Was knock-out (WKO) mice have shown that WASp plays a critical role in the function of T and natural killer lymphocytes and dendritic cells. 1,3 However, the importance of WASp in B-cell development and function is less clearly defined. In vitro studies have shown that WASp-deficient B cells display defective actin polymerization on activation, 4 and impaired migration in response to CXCL13 5 ; however, calcium mobilization and proliferation after B-cell receptor ligation were found to be normal or only slightly reduced. 3 Studies in heterozygous Was ϩ/Ϫ mice have found progressive in vivo selection for WASp-expressing cells in T, B, and natural killer lineages. 6 Within the B-cell lineage, such selective advantage was especially prominent in marginal zone (MZ) B cells. 2,6 However, the in vivo effect of selective deficiency of WASp expression within a single lineage has not been analyzed so far and is of critical importance to understand WAS pathophysiology. Recently, with the use of a chimeric BM transplantation reconstitution model, Becker-Herman et al have provided evidence that lack of WASp expression in B lymphocytes causes immune dysregulation and may lead to fatal autoimmunity. 7 However, mixed chimerism in non-B lineages, irradiation-induced load of The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. 2819BLOOD, 22 MARCH 2012 ⅐ VOLUME 119, NUMBER 12For personal use only. on May 9, 2018. by guest www.bloodjournal.org From apoptotic bodies, and homeostatic B-cell proliferation may also have contributed to autoimmunity in that model.We describe here the generation of mice in which the Was locus has been floxed by homologous recombination. By crossing these mice to mb1-Cre knock-in mice, 8 which express the Cre recombinase under control of the CD79a promoter, the Was locus is selectively and efficiently deleted in B cells only, allowing analysis of the effect of B cell-restricted deficiency of WASp in vivo. Methods MiceAll mice were bred on a C57BL/6 background. WKO mice have been described. 3 Mb1-Cre mice 8 were a generous gift from Dr Michael Reth (Max Planck Institute of Immunobiology, ...

Currently licensed pneumococcal vaccines are based on the generation of antibodies to the pneumococcal polysaccharide, of which there are more than 90 different types. While these vaccines are highly effective against the serotypes included, their high cost and limited serotype coverage limits their usefulness worldwide, particularly in low resources areas. Thus alternative or adjunctive options are being actively pursued. This review will present these various approaches, including variations of the polysaccharide-protein conjugate strategy, protein-based strategies, and an inactivated whole cell pneumococcal vaccine. The immunological basis for these different approaches is discussed as well.