Adjuvant Activities of Novel Cytokines, Interleukin-23 (IL-23) and IL-27, for Induction of Hepatitis C Virus-Specific Cytotoxic T Lymphocytes in HLA-A*0201 Transgenic Mice

Abstract

CD8ϩ cytotoxic T lymphocytes (CTLs) recognize virus-derived peptides in association with major histocompatibility complex class I molecules on the surface of antigen-presenting cells and kill the virus-infected target cells. There are a number of evidences showing that CTLs play a central role in the clearance of pathogenic viruses (67). In case of hepatitis C virus (HCV) infection, vigorous HCV-specific CTL responses existed in the persons resolving acute HCV infection (27). In the experimental model, chimpanzees who cleared HCV generated strong CTL but poor antibody responses, whereas other chimpanzees developing chronic hepatitis generated much weaker CTL response (12). Thus, spontaneous resolution of HCV is likely to be associated with HCV-specific CTLs rather than neutralizing antibodies (12,18,27,58). However, Ͼ60% of HCV-infected individuals turn out to have chronic hepatitis (1). Chronic HCV hepatitis eventually progresses to cirrhosis and hepatocellular carcinoma (53). In the chronic stage, HCVspecific CTLs are detectable in both peripheral blood and liver, but the precursor frequency of HCV-specific CTLs is extremely low (27,50,51). Therefore, enhancement of HCVspecific CTL induction in HCV-infected individuals should be considered to be a strategy to clear the virus. DNA vaccination has been proven to be a useful strategy for inducing both humoral and cellular immune responses (19). DNA vaccine safely mimics the effect of live, attenuated virusbased vaccine to generate a long-lasting CTL response. However, the efficiency of DNA vaccine is sometimes quite low and, therefore, several modifications have been attempted in recent years (19). Thus far, the most successful protocol of DNA immunization for CTL induction is likely to be a consecutive immunization involving priming with plasmid DNA and boosting with recombinant virus (2,24,35,43,54). The rationale behind this strategy is that DNA priming elicits low-level but persistent immunity, followed by strong boosting with virus encoding the same recombinant antigen as the DNA encodes. This regimen of the consecutive immunization has been proven to be efficient for CTL induction by many groups (2,24,35,37,43,54). Recently, McConkey et al. (37) have shown that the prime-boost immunization induced high frequencies of antigen-specific T-cell responses to malaria antigen and displayed partial protection in humans.Interleukin-12 (IL-12) is a heterodimeric proinflammatory cytokine formed by a 35-kDa light chain (p35) and a 40-kDa heavy chain (p40) (57). This cytokine is a dominant factor in the differentiation of T helper type 1 (Th1) cells and plays an essential role in a link between innate and adaptive immunities (60). Recently, two novel polypeptides, p19 (42) and p28 (48), have been identified by searching the databases with a computationally derived profile of IL-6. These factors do not show

Augmentation of Effector CD8+ T Cell Generation with Enhanced Granzyme B Expression by IL-27

“…Recently, we have found that IL-27 has a potent ability to induce tumor-specific antitumor activity, which is mainly mediated through CD8 ϩ T cells with enhanced CTL activity (11), and also that IL-27 has a potent adjuvant activity for the induction of HCVspecific CTLs (12). Consistent with these two studies indicating that IL-27 augments CTL activity in vivo, we have shown in this study that IL-27 directly acts on naive CD8…”

“…Moreover, we have evaluated the adjuvant activity of IL-27 expression plasmid in the prime-boost immunization consisting of an hepatitis C virus (HCV) core expression plasmid and a recombinant adenovirus-expressing HCV core, and elucidated that IL-27 has a potent adjuvant activity for the induction of HCV-specific CTLs (12). These two studies clearly indicate that IL-27 augments CTL activity in vivo, whereas little is known on the molecular mechanism underlying the augmentation of CTL activity by IL-27.…”

Impact of HIV Infection and HAART Therapy on CD4 T Helper Cell Subset Expression and Function

“…In the study by Lee et al, mRNA levels of p19 were examined whereas Louis et al examined secreted IL-23, which may partially explain the observed discrepancy. In 2004, a study revealed that IL-23 has potent adjuvant effects on induction of epitope-specific cytotoxic T lymphocytes (CTLs) (Matsui, Moriya et al, 2004). The authors found that coadministration of an IL-23 expression plasmid in a prime-boost immunization enhanced the induction of Hepatitis C virus (HCV)-specific CTLs in mice.…”

IL-23 Enhances Host Defense against Vaccinia Virus Infection Via a Mechanism Partly Involving IL-17

“…This expression vector encodes the preprotrypsin signal peptide and the 3xFLAG-epitope-tag sequence upstream of the multiple cloning region and, hence, expresses a secreted N-terminal 3xFLAG fusion protein in mammalian cells. Conversely, the murine IL-12 (p3xFLAG-IL-12) and murine IL-23 (p3xFLAG-IL-23) expression plasmids, which include murine single-chain (sc)IL-12 and murine scIL-23 genes, respectively, had previously been constructed (6). The scIL-12 and scIL-23 genes are composed of p40 genetically fused with p35 and p19, respectively (6).…”

“…Conversely, the murine IL-12 (p3xFLAG-IL-12) and murine IL-23 (p3xFLAG-IL-23) expression plasmids, which include murine single-chain (sc)IL-12 and murine scIL-23 genes, respectively, had previously been constructed (6). The scIL-12 and scIL-23 genes are composed of p40 genetically fused with p35 and p19, respectively (6). The biological activity of each single-chain cytokine was shown to be almost similar to that of the native heterodimeric cytokine (4,5).…”