The immunoregulatory role of CD244 in chronic hepatitis B infection and its inhibitory potential on virus-specific CD8+ T-cell function

Abstract

Multiple inhibitory receptors may play a role in the weak or absent CD81 T-cell response in chronic hepatitis B virus (HBV) infection. Yet few receptors have been characterized in detail and little is known about their complex regulation. In the present study, we investigated the role of the signaling lymphocyte activation molecule (SLAM)-related receptor CD244 and of programmed death 1 (PD-1) in HBV infection in 15 acutely and 66 chronically infected patients as well as 9 resolvers and 21 healthy controls. The expression of CD244, PD-1, and T-cell immunoglobulin domain and mucin domain 3 (TIM-3) was analyzed in virus-specific CD81 T-cells derived from peripheral blood or liver using major histocompatibility complex class I pentamers targeting immunodominant epitopes of HBV, Epstein-Barr-virus (EBV), or influenza virus (Flu). In chronic HBV infection, virusspecific CD81 T-cells expressed higher levels of CD244 both in the peripheral blood and liver in comparison to the acute phase of infection or following resolution. CD244 was expressed at similarly high levels in EBV infection, but was low on Flu-specific CD81 Tcells. In chronic HBV infection, high-level CD244 expression coincided with an increased expression of PD-1. The inhibition of the CD244 signaling pathway by antibodies directed against either CD244 or its ligand CD48 resulted in an increased virus-specific proliferation and cytotoxicity as measured by the expression of CD107a, interferon-c, and tumor necrosis factor-a in CD81 T-cells. Conclusion: CD244 and PD-1 are highly coexpressed on virus-specific CD81 T-cells in chronic HBV infection and blocking CD244 or its ligand CD48 may restore T-cell function independent of the PD-1 pathway. CD244 may thus be another potential target for immunotherapy in chronic viral infections.

Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

“…14,44 Persistent HBV infection impairs HBV-specific CD8 1 T-cell function and results in the exhausted-phenotype CD8 1 cells that fail to clear virus. 45,46 In our study, our results demonstrate that blockage of TNF-a leads to increasing liver-infiltrating PD-1 high CD127 low -exhausted phenotype CD8 1 T cells in mice with HBV persistence. These results indicate that in HBV persistence, blockage of TNF-a will further impair the adaptive immune response and that TNF-a is crucial for maintaining an effective anti-HBV immune response.…”

Long noncoding RNA derived from CD244 signaling epigenetically controls CD8 + T-cell immune responses in tuberculosis infection

“…It has recently been shown that CD244 is expressed on virus-specific CD8 + T cells (9,(39)(40)(41) and that CD244 signaling correlates with viral persistence of hepatitis B virus (HBV) and HCV in humans (9,39,40). However, little is known about the molecular mechanism and consequence for CD244 regulation of T-cell effector functions during active TB infection.…”

Augmentation of Hepatitis B Virus-Specific Cellular Immunity with Programmed Death Receptor-1/Programmed Death Receptor-L1 Blockade in Hepatitis B Virus and HIV/Hepatitis B Virus Coinfected Patients Treated with Adefovir

“…15 Tregs, demarcated by CD4 + CD24 + FoxP3 + expression, 16 inhibit effective virus-specific immune responses 17,18 and can also express programmed death receptor-1 (PD-1), which further deters immune responses when expressed on CD4 + , CD8 + , NK T cells, monocytes, or B cells. [19][20][21][22][23] In this study, we investigated the immunoregulatory mechanisms that suppress HBV-specific immunity in HIV-positive and HIVnegative CHB patients and explored methods to augment the HBV-specific immune response thereby enhancing the potential for HBV eradication.…”