CD28 family of receptors on T cells in chronic HBV infection: Expression characteristics, clinical significance and correlations with PD-1 blockade

Abstract

The aim of the present study was to investigate the overall clinical expression characteristics of the cluster of differentiation (CD)28 family receptors [CD28, inducible T-cell co-stimulator, programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 and B- and T-lymphocyte attenuator] on T cells in patients with chronic hepatitis B (CHB), analyze the correlations among these receptors and the clinical parameters, and to investigate the effects of PD-1 blockade on the receptor expression profiles, T-cell function and other biological effects. The expression characteristics of the CD28 family of receptors, the effects of PD-1 blockade on the receptor expression profiles and the levels of interferon (IFN)-γ were investigated in the T cells of patients with CHB. In addition, the transcription factor, T-box 21 (T-bet) and GATA binding protein 3 (GATA-3) mRNA expression levels were investigated in the peripheral blood mononuclear cells (PBMCs) of patients with CHB. The expression levels of the CD28 family receptors in the T cells of patients with CHB demonstrated distinct characteristics, for example levels of PD-1 and CTLA-4 on CD4 T cells and ICOS, PD-1, and BTLA on CD8 T cells were increased in cells from patients with CHB compared with those from the healthy individuals. A significant positive correlation was demonstrated among the serum HBV DNA titers and the levels of PD-1 on CD8+ T cells with the highest expression of PD-1 corresponding to viral levels >106 IU/ml. A significant positive correlation was observed between the serum HBV DNA titers and the expression levels of BTLA on CD8+ T cells with the highest expression of BTLA corresponding to viral levels >106 IU/ml. PD-1 blockade altered the expression profiles of CD28 family receptors in the T cells of patients with CHB, partly enhanced T cell function and increased the ratio of T-bet/GATA-3 mRNA in PBMCs. Thus, CD28 family receptors are potential clinical indicators for the rapid monitoring of changes in T cell function during CHB treatment. Furthermore, PD-1 blockade has a therapeutic potential that may be enhanced by modulating the expression of co-stimulatory and -inhibitory receptors of the CD28 family.

Immune checkpoints and their inhibition in cancer and infectious diseases

“…Antiviral therapy in the form of oral direct antiviral agents (telbivudine or lamivudine) reduced expression of PD‐1 on T cells, which was associated with enhanced IFN‐γ and reduced IL‐10 secretion . Blockade of PD‐1 during ex vivo restimulation of PBMCs from patients with chronic HBV infection increased IFN‐γ secretion by CD4 + but not CD8 + T cells . Similarly, TIM‐3 overexpression was associated with reduced IFN‐γ secretion by CD8 + T cells from HBV‐infected patients and this was partially enhanced by blocking the TIM‐3 pathway .…”

Immune checkpoints in chronic obstructive pulmonary disease

“…Better reconstitution of T-cell function is seen when multiple receptors are blocked, suggesting synergistic signalling effects [30]. Similar patterns of cellular expression and T-cell exhaustion have been demonstrated in an array of chronic infections in humans, most notably in tuberculosis [31], HIV [32] and chronic viral hepatitis [16]. Interestingly, T-cell exhaustion has been described in conditions associated with autoimmunity, such as rheumatoid arthritis, suggesting a protective role of checkpoint pathways in this context [33].…”

“…Here, the role of cytotoxic T-lymphocyte-associated antigen (CTLA)-4 has been established as an important control of T-cell function early in the activation cycle [15]. In addition, these immune checkpoint receptors, which are part of the CD28 family of cell surface receptors [16], play a significant role in controlling the cell-mediated response in tissues where both antigen-presenting cells (APCs) and structural cells may express checkpoint ligands, and both antigenic stimulation and checkpoint ligand expression contribute to a fine equipoise of immune activation and control [17,18]. Here the programmed death (PD)1 receptor has an established role, in limiting T-cell effector function, especially cytotoxic activity [19].…”

The Influence of B and T Lymphocyte Attenuator Genetic Variants on Susceptibility to Chronic Hepatitis B Virus Infection

“…In chronic hepatitis B patients, the expression of BTLA increases in intrahepatic specific CD8+ T cells and is associated with the dysfunction of cytotoxic T cells [14-16]. Blockade of the BTLA pathway can partially restore the function of viral specific CD8+ T cells and enhance their proliferation [15, 17].…”