Tapasin modification on the intracellular epitope HBcAg18–27 enhances HBV-specific CTL immune response and inhibits hepatitis B virus replication in vivo

Abstract

HBV-specific cytotoxic T-lymphocyte (CTL) activity has a very important role in hepatitis B virus clearance. Present studies suggest that Tapasin, a endoplasmic reticulum (ER) chaperone, stabilizes the peptide-receptive MHC I conformation, allowing peptide exchange and increasing more peptides to be translocated into the ER. We have previously testified that cytoplasmic transduction peptide (CTP)-HBcAg 18-27 -Tapasin fusion protein could enter cytoplasm of dendritic cells, and enhance T cells' response to generate specific CTLs efficiently in vitro. In the present study, we evaluated specific immune responses of CTP-HBcAg 18-27 -Tapasin fusion protein in HLA-A2 transgenic mice (H-2K b ) and anti-viral ability in HBV transgenic mice, and explored the mechanisms probably involved in. The studies showed that CTP-HBcAg 18-27 -Tapasin not only increased production of cytokine IFN-g and interleukin-2 (IL-2), compared with CTP-HBcAg 18-27 , HBcAg 18-27 -Tapasin, and PBS, but also significantly induced the higher percentages of IFN-g þ CD8 þ T cells and specific CTL responses in HLA-A2 transgenic mice. Moreover, enhancement of specific CTL activity induced by the fusion protein reduced HBV DNA and hepatitis B surface antigen (HBsAg) levels and decreased the expression of HBsAg and hepatitis B core antigen (HBcAg) in liver tissue of HBV transgenic mice. In addition, CTP-HBcAg 18-27 -Tapasin could upregulate the expression of JAK2, Tyk2, STAT1, and STAT4 in T lymphocytes in HLA-A2 transgenic mice splenocytes. However, there was no significant difference on the expressions of JAK1, JAK3, and STAT6 between each group. In conclusion, CTP-HBcAg 18-27 -Tapasin fusion protein could enhance not only the percentages of CTLs but also induce robust specific CTL activity and inhibits hepatitis B virus replication in vivo, which was associated with activation of the JAK/STAT signaling pathway. Hepatitis B virus (HBV) infection remains a global problem, despite the effectiveness of the HBV vaccines in preventing infection. Although the factors that contribute to the clearance of the virus in acute self-limiting HBV infection or to the persistence of the virus in chronic HBV infection are not completely clear, increasing evidence suggests that host immune responses are an important factor in determining the outcome of HBV infection. 1,2 Acute individuals develop a strong, polyclonal, multispecific cytotoxic T-lymphocyte (CTL) response and a polyclonal T helper (Th) cell response to the virus typically, while these responses are markedly attenuated in chronically infected patients. 3,4 Persistent HBV infection is characterized by a weak adaptive immune response, thought to be due to inefficient CD4 þ T-cell priming in the early stage of virus infection and subsequent development of a quantitatively and qualitatively ineffective CD8 þ T-cell response. Studies of HBV infection in woodchucks and chimpanzees, as well as patients, are suggesting that multiple and frequent administration of the vaccine may be advisable in treatment of chronic...

Corticosteroid therapy in IgA nephropathy with minimal proteinuria and high renal pathological score: A single‑center cohort study

“…The JAK/STAT signaling pathway mediates the biological responses induced by numerous cytokines, and it is particularly important for differentiation of helper T-cells. Cytokines bind to the cell surface receptors of immune and non-immune cells to activate the JAK-STAT signaling pathway, which affects the function of CD4 -T-cells by upregulating the expression of specific target genes (44)(45)(46). In the present study, assays were performed to detect the levels of T-cell cytokines in serum samples and JAK/STAT pathway proteins in the PBMCs of all patients with IgAN prior to treatment and in the healthy control group (49 healthy subjects were selected as the normal control group) There was no significant difference in sex and age between the patients with IgAN and the control group (Table I).…”

Correlation between low tapasin expression and impaired CD8+ T-cell function in patients with chronic hepatitis B

“…Our previous study demonstrated that tapasin modification on the intracellular epitope HBcAg 18-27 via CTP could enter the cytoplasm of BMDCs, thus promoting BMDC maturation, and efficiently enhancing the T-cell immune response in vitro (1). Furthermore, the CTP-HBcAg 18-27 -Tapasin fusion protein was able to enhance the percentage of CTLs, induce robust specific CTL activity, reduce apoptosis of CD8 + T cells and inhibit HBV replication in vivo (10,11). These findings suggested that tapasin may be a key factor in the process of HBV clearance.…”

“…Our previous study demonstrated that the expressed and purified fusion protein cytoplasmic transduction peptide (CTP)-HBV core antigen (HBcAg) 18-27 -Tapasin could enter the cytoplasm of bone marrow-derived dendritic cells (BMDCs), promoting BMDC maturation and efficiently enhancing the T-cell immune response in vitro (1). Furthermore, the CTP-HBcAg 18-27 -Tapasin fusion protein could enhance the percentage of CTLs, induce robust specific CTL activity, reduce apoptosis of CD8 + T cells and inhibit HBV replication in vivo (10,11). It has also been demonstrated that chronic HBV (CHB) infection is associated with reduced antigen-presenting capacity and insufficient CTL production (12).…”

T lymphocytes in IgA nephropathy (Review)

“…CD4 + T cells, including Treg and effector Th cells, play a key role in the host defense. However, the imbalance of CD4 + T cell differentiation leads to chronic infections as well as a variety of inflammatory allergic and autoimmune diseases, such as chronic hepatitis B virus infection (25), rhinallergosis (26) and IgAN (27). The differentiation and functions of CD4 + T cell subsets are dependent upon the cytokine environment, which enables the differentiation into several distinct subtypes to coordinate the immune response to clear the pathogenic insult.…”