Many pathogens, including Plasmodium spp., exploit the interaction of programmed death-1 (PD-1) with PD-1-ligand-1 (PD-L1) to "deactivate" T cell functions, but the role of PD-L2 remains unclear. We studied malarial infections to understand the contribution of PD-L2 to immunity. Here we have shown that higher PD-L2 expression on blood dendritic cells, from Plasmodium falciparum-infected individuals, correlated with lower parasitemia. Mechanistic studies in mice showed that PD-L2 was indispensable for establishing effective CD4(+) T cell immunity against malaria, because it not only inhibited PD-L1 to PD-1 activity but also increased CD3 and inducible co-stimulator (ICOS) expression on T cells. Importantly, administration of soluble multimeric PD-L2 to mice with lethal malaria was sufficient to dramatically improve immunity and survival. These studies show immuno-regulation by PD-L2, which has the potential to be translated into an effective treatment for malaria and other diseases where T cell immunity is ineffective or short-lived due to PD-1-mediated signaling.

ABSTRACTmolecules is ideally suited for the capture of lipid antigens 3 . CD1 clefts derive from deep invaginations into the CD1 core structure and form two or four pockets 5,6,7,8,9. In general, the pockets surround a large portion of the lipidic antigens so that their hydrocarbon moieties are sequestered from solvent and the hydrophilic headgroups protrude for T cell contact. However, each of the four types of human CD1 proteins has a cavity with unique architecture, which endows each CD1 isoform with the ability to present specific types of lipids. Whereas MHC proteins allow broad access to peptides that span the entire platform, CD1 proteins possess an

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Basic parameters of the naive antigen (Ag)-specific T-cell repertoire in humans remain poorly defined. Systematic characterization of this ‘ground state' immunity in comparison with memory will allow a better understanding of clonal selection during immune challenge. Here, we used high-definition cell isolation from umbilical cord blood samples to establish the baseline frequency, phenotype and T-cell antigen receptor (TCR) repertoire of CD8+ T-cell precursor populations specific for a range of viral and self-derived Ags. Across the board, these precursor populations were phenotypically naive and occurred with hierarchical frequencies clustered by Ag specificity. The corresponding patterns of TCR architecture were highly ordered and displayed partial overlap with adult memory, indicating biased structuring of the T-cell repertoire during Ag-driven selection. Collectively, these results provide new insights into the complex nature and dynamics of the naive T-cell compartment.

CD96 has recently been shown to be a potent immune checkpoint molecule in mice, but a similar role in humans is not known. In this study, we provide a detailed map of CD96 expression across human lymphocyte lineages, the kinetics of CD96 regulation on T-cell activation and co-expression with other conventional and emerging immune checkpoint molecules. We show that CD96 is predominantly expressed by T cells and has a unique lymphocyte expression profile. CD96 T cells exhibited distinct effector functions on activation. Of note, CD96 expression was highly correlated with T-cell markers in primary and metastatic human tumors and was elevated on antigen-experienced T cells and tumor-infiltrating lymphocytes. Collectively, these data demonstrate that CD96 may be a promising immune checkpoint to enhance T-cell function against human cancer and infectious disease.

Polypeptide vaccines effectively activate human T cells but suffer from poor biological stability, which confines both transport logistics and in vivo therapeutic activity. Synthetic biology has the potential to address these limitations through the generation of highly stable antigenic “mimics” using subunits that do not exist in the natural world. We developed a platform based on D–amino acid combinatorial chemistry and used this platform to reverse engineer a fully artificial CD8+ T cell agonist that mirrored the immunogenicity profile of a native epitope blueprint from influenza virus. This nonnatural peptide was highly stable in human serum and gastric acid, reflecting an intrinsic resistance to physical and enzymatic degradation. In vitro, the synthetic agonist stimulated and expanded an archetypal repertoire of polyfunctional human influenza virus–specific CD8+ T cells. In vivo, specific responses were elicited in naive humanized mice by subcutaneous vaccination, conferring protection from subsequent lethal influenza challenge. Moreover, the synthetic agonist was immunogenic after oral administration. This proof-of-concept study highlights the power of synthetic biology to expand the horizons of vaccine design and therapeutic delivery.

Genomics Data Miner (GMine) is a user-friendly online software that allows non-experts to mine, cluster and compare multidimensional biomolecular datasets. Various powerful visualization techniques are provided, generating high quality figures that can be directly incorporated into scientific publications. Robust and comprehensive analyses are provided via a broad range of data-mining techniques, including univariate and multivariate statistical analysis, supervised learning, correlation networks, clustering and multivariable regression. The software has a focus on multivariate techniques, which can attribute variance in the measurements to multiple explanatory variables and confounders. Various normalization methods are provided. Extensive help pages and a tutorial are available via a wiki server. Using GMine we reanalyzed proteome microarray data of host antibody response against Plasmodium falciparum. Our results support the hypothesis that immunity to malaria is a higher-order phenomenon related to a pattern of responses and not attributable to any single antigen. We also analyzed gene expression across resting and activated T cells, identifying many immune-related genes with differential expression. This highlights both the plasticity of T cells and the operation of a hardwired activation program. These application examples demonstrate that GMine facilitates an accurate and in-depth analysis of complex molecular datasets, including genomics, transcriptomics and proteomics data.

Synthetic hookworm-derived peptides are potent modulators of primary human immune cell function that protect against experimental colitis in vivo