Enhancement of Vaccine-induced Primary and Memory CD8+ T-cell Responses by Soluble PD-1

Abstract

Programmed death 1 (PD-1) signaling through its ligands, PD-L1 and PD-L2, has been known to negatively regulate T-cell responses. In addition, PD-L1 has been shown to interact with B7-1 costimulatory molecule to inhibit T-cell responses. Extensive studies have shown that PD-1/PD-L blockade restores exhausted T cells during chronic viral infections and tumors. In this study, we evaluated the effects of soluble PD-1 (sPD-1) as a blockade of PD-1 and PD-L1 on vaccine-elicited antigen-specific T-cell responses in mice. Coadministration of sPD-1 DNA with human papilloma virus-16 E7 DNA vaccine significantly enhanced E7-specific CD8(+) T-cell responses, resulting in potent antitumor effects against E7-expressing tumors. We also found that sPD-1, codelivered with adenovirus-based vaccine, could increase antigen-specific CD8(+) T-cell responses, indicating vaccine type-independent adjuvant effect of sPD-1. In addition, the frequency and functional activity of adoptively transferred OT-I cells, particularly memory CD8(+) T cells, were augmented by coadministration of sPD-1 DNA, which was closely associated with increased T-cell proliferation and reduced T-cell apoptosis through upregulation of Bcl-xL expression during T-cell activation. Codelivery of sPD-1 DNA also enhanced maturation of dendritic cells (DCs) in vivo which was accompanied by upregulation of DC maturation markers such as major histocompatibility complex class II. Taken together, our findings show that sPD-1 potently enhances codelivered antigen-specific CD8(+) T-cell responses and in vivo maturation of DCs during activation of naive CD8(+) T cells, suggesting that an immunization strategy with sPD-1 as an adjuvant can be used to increase antigen-specific T-cell immunity elicited by vaccination.

Role of soluble programmed death-1 (sPD-1) and sPD-ligand 1 in patients with cystic echinococcosis

“…Any imbalances in this regulatory mechanism may dysregulate the immune responses. The expression of sPD-1 is known to inhibit PD-L1 in various cell types in mice (23,25), including molecules expressing PD-L1 as a result of a CE infection and PD-L1 molecules associated with T cell apoptosis, thereby increasing the secretion of cytokines.…”

Antibodies to gp120 and PD-1 Expression on Virus-Specific CD8 + T Cells in Protection from Simian AIDS

“…Extensive studies have shown that a PD-1/PD-L1 blockade restores exhausted T cells during chronic viral infections and in tumors (28,55). Song et al evaluated the effects of soluble PD-1 (sPD-1) as a blockade of PD-1 and PD-L1 on vaccine-elicited antigen-specific T-cell responses in mice (56). Coadministration of sPD-1 with an Ad-based vaccine could increase antigen-specific CD8 ϩ T-cell responses, indicating a vaccine type-independent adjuvant effect of sPD-1.…”

“…PPP2R5C is implicated in the negative control of cell growth and division (54,57). ATF2 and ATF4 have proapoptotic activity and are involved in the upregulation of Fas and FasL (56). PTEN is known to inhibit AKT phosphorylation, involved in phosphorylation of FOXO3a in different cell models (58) as well as it negatively regulates the activation of NF-B and I kinase ␤ (IKK␤) (59).…”

Biomaterials at the interface of nano- and micro-scale vector–cellular interactions in genetic vaccine design

“…81–83 Emphasizing co-stimulatory molecules, blockage of the receptors through expression of inhibitors or siRNA can assist in the regulation of immune responses that are present during chronic viral infection and cancer. 84, 85 In summary, the diversity and specificity of molecular adjuvants holds enormous potential and will likely continue to receive significant attention on the basis of encouraging preliminary results reported in the clinic.…”