HBcAg induces PD-1 upregulation on CD4+T cells through activation of JNK, ERK and PI3K/AKT pathways in chronic hepatitis-B-infected patients

Abstract

Hyper-expression of programmed death-1 (PD-1) is a hallmark of exhausted T cells. In chronic hepatitis-B virus (HBV)-infected patients, PD-1 upregulation on T cells was often observed. The mechanism of it has not been fully understood. In this study, we examined the dynamic changes of PD-1 expression on T cells during the natural history of chronic HBV infection and explored the signaling pathway of PD-1 upregulation by the hepatitis-B core antigen (HBcAg). Sixty-seven chronic HBV-infected patients were categorized into an immune tolerance group, an immune clearance group and an inactive virus carrier group, and 20 healthy volunteers were chosen as normal control group. Peripheral blood mononuclear cells from patients and healthy volunteers, and T lymphocytes from healthy volunteers were separated. Results showed that the PD-1 expression level on CD4 þ T cells in every phase of chronic HBV infection was significantly higher than that in healthy volunteers, whereas such effects were not observed on CD8 þ T cells. In the immune clearance phase, a positive correlation was found between serum HBV DNA level and the PD-1 expression level on CD4 þ T cells. In all phases, no correlation was shown between serum alanine amino transferase (ALT) level and PD-1 expression level. Phosphorylation of JNK, ERK and AKT was induced by HBcAg, and inhibitors of JNK, ERK and PI3K/AKT significantly decreased the HBcAg-induced PD-1 upregulation on CD4 þ T cells. In conclusion, the PD-1 expression level on CD4 þ T cells was upregulated in every phase of chronic HBV infection, which was induced by HBcAg through JNK, ERK and PI3K/AKT signaling pathways.

The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia

“…39 Expression of PD-1 on the neoplastic counterpart was reported in a limited number of diffuse large B-cell lymphomas and in a more significant number of small lymphocytic lymphomas. A fraction of circulating CLL cells is also reported as PD-1 + (see Grzywnowicz et al 17 and Li et al 18 and confirmed in this work) even if the prognostic and functional implications remain unknown.…”

“…[18][19][20] On the contrary, PD-1 is classically considered a marker of cell exhaustion in the CD8 subset. 21 Thus, the finding of an increased expression of PD-1 in T lymphocytes from CLL patients suggests a relative enrichment in terminally differentiated cells as compared to controls with a similar age.…”

Hepatitis B Virus Core Antigen Stimulates IL-6 Expression via p38, ERK and NF-κB Pathways in Hepatocytes

“…HBcAg, which is composed of 183 residues with a 21 kDa molecular weight, is not only required for productive HBV lifecycle, but also elicit diverse responses from the host cells, due to its potent immunogenicity [4, 5, 30-34]. The strong immunogenicity of HBcAg was suggested by the stimulation of TNF-α production in IHLs [5], increase of TNF-α, IL-12p40 and IL-6 expression in human THP-1 macrophages [35], and induction of IL-10, IL-17A, IL-22, IL-23, IL-6 and IL-18 production in PBMCs [3, 36, 37], when HBcAg was exposed to those cells.…”

“…HBcAg negatively regulates HBcAg-specific T-helper (Th) 17cell responses [3], inhibits host antiviral immunity through upregulating the expression of programmed death-1 (PD-1) on CD4 + T cells [4]. On the other hand, HBcAg induced intra-hepatic leukocytes (IHLs) to produce tumor necrosis factor alpha (TNF-α) which is helpful for virus clearance [5].…”

PD-1 and CTLA-4 Mediated Inhibitory Signaling for T cell Exhaustion during Chronic Viral Infections

“…In addition, there is a positive correlation between serum HBV DNA levels and the PD-1 expression levels on CD4 + T cells in the immune clearance phase. In vitro assay further shows that Hepatitis B Core Antigen (HBcAg) induces PD-1 expression on T cells, and inhibitors against JNK, ERK and PI3K/ AKT significantly decrease HBcAg-induced PD-1 expression on CD4 + T cells [20]. Interestingly, several reports demonstrate that anti-viral cytokine IFN-α promotes the induction and maintenance of PD-1 expression through an association of IFN-responsive factor 9 (IRF9) to the IFN stimulation response element on the pdcd1 promoter in T cells [21].…”