Programmed cell death-1 (PD-1) is a member of the CD28 superfamily that delivers negative signals upon interaction with its two ligands, PD-L1 or PD-L2. PD-1 and its ligands are broadly expressed and exert a wider range of immunoregulatory roles in T cells activation and tolerance compared with other CD28 members. Subsequent studies show that PD-1-PD-L interaction regulates the induction and maintenance of peripheral tolerance and protect tissues from autoimmune attack. PD-1 and its ligands are also involved in attenuating infectious immunity and tumor immunity, and facilitating chronic infection and tumor progression. The biological significance of PD-1 and its ligand suggests the therapeutic potential of manipulation of PD-1 pathway against various human diseases. In this review, we summarize our current understanding of PD-1 and its ligands ranging from discovery to clinical significance.

Summary To design successful vaccines for chronic diseases, an understanding of memory CD8+ T cell responses to persistent antigen re-stimulation is critical. However, most studies comparing memory and naïve cell responses have only been performed in rapidly cleared acute infections. Herein, by comparing the responses of memory and naïve CD8+ T cells to acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we show that memory cells dominated over naïve cells and were protective when present in sufficient numbers to quickly reduce infection. In contrast, when infection was not rapidly reduced, memory cells were quickly lost, unlike naïve cells. This occurred with both transgenic and endogenous memory CD8+ T cells, and with memory cells initially generated by different vaccines. This loss of memory cells was due to a block in sustaining cell proliferation, selective regulation by the inhibitory receptor 2B4, and increased reliance on CD4+ T cell help. Thus, emphasizing the importance of designing vaccines that elicit effective CD4+ T cell help and rapidly control infection.

Here, we demonstrate that electroporation-enhanced immunization with a rationally designed HPV DNA vaccine (GX-188E), preferentially targeting HPV antigens to dendritic cells, elicits a significant E6/E7-specific IFN-γ-producing T-cell response in all nine cervical intraepithelial neoplasia 3 (CIN3) patients. Importantly, eight out of nine patients exhibit an enhanced polyfunctional HPV-specific CD8 T-cell response as shown by an increase in cytolytic activity, proliferative capacity and secretion of effector molecules. Notably, seven out of nine patients display complete regression of their lesions and viral clearance within 36 weeks of follow up. GX-188E administration does not elicit serious vaccine-associated adverse events at all administered doses. These findings indicate that the magnitude of systemic polyfunctional CD8 T-cell response is the main contributing factor for histological, cytological and virological responses, providing valuable insights into the design of therapeutic vaccines for effectively treating persistent infections and cancers in humans.

SUMMARY The inhibitory receptor Tim-3 has emerged as a critical regulator of the T cell dysfunction that develops in chronic viral infections and cancers. However, little is known regarding the signaling pathways that drive Tim-3 expression. Here, we demonstrate that IL-27 induces NFIL3, which promotes permissive chromatin remodeling of the Tim-3 locus and induces Tim-3 expression together with the immunosuppressive cytokine IL-10. We further show that the IL-27/NFIL3 signaling axis is crucial for the induction of Tim-3 in vivo. IL-27-conditioned Th1 cells exhibit reduced effector function and are poor mediators of intestinal inflammation. This inhibitory effect is NFIL3 dependent. In contrast, tumor-infiltrating lymphocytes (TILs) from IL-27R−/− mice exhibit reduced NFIL3, less Tim-3 expression and failure to develop dysfunctional phenotype, resulting in better tumor growth control. Thus, our data identify an IL-27/NFIL3 signaling axis as a key regulator of effector T cell responses via induction of Tim-3, IL-10, and T cell dysfunction.

A t least 170 million people worldwide are persistently infected with hepatitis C virus (HCV), which is the most common reason for liver transplantation. An estimated 2.3 to 4.7 million people become newly infected every year, but an effective vaccine is not yet available. 1,2 Six different genotypes and a variety of quasispecies of HCV pose a major challenge for the development of an effective HCV vaccine. At present the chimpanzee is the only reliable experimental animal model in which to investigate the early events after HCV infection and to evaluate the efficacy of vaccine candidates. Since HCV-specific T-cell immunity has been known to be important in the control of HCV infection, 3-5 a substantial effort has been focused on the induction of vigorous HCV-specific T-cell immunity. Although a neutralizing antibody was considered to be crucial for vaccine-mediated protection against initial virus infection by blunting the infection at an early stage, 6 there have been few reports demonstrating the role of the antibody in the prevention of HCV infection. Vaccination with recombinant E1/E2 proteins in chimpanzees, albeit transient, induced strong antibody responses that were responsible for the prevention of a low dose of ho-