Functional restoration of CD56 NK cells facilitates immune control via IL-15 and NKG2D in patients under antiviral treatment for chronic hepatitis B.

BACKGROUND AND AIMS

Hepatitis B virus (HBV) is intrinsically immunogenic, with long-lasting immune control in many patients. However, the mechanisms and key cell types underlying effective immune control are incompletely understood.

METHODS

We studied the restoration of natural killer (NK) cell numbers and function post antiviral treatment in 52 hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients who received telbivudine (LdT) for 48 weeks. Blood samples were collected at week 0, 12, 24, 36, and 48 and tested for HBV DNA, hepatitis B surface antigen (HBsAg), HBeAg, liver enzymes, and NK cell parameters.

RESULTS

Compared with baseline, the number of peripheral CD3CD56 NK cells increased significantly from week 24 to 48, especially in patients with baseline alanine transaminase (ALT) two- to fivefold the upper line of normal (ULN) or HBV DNA <9 log copies/ml. Expression (number and density) of activating receptors NKG2D and NKp46 on CD3CD56 NK cells was enhanced, while inhibitory receptor NKG2A decreased. Notably, numbers of CD3CD56 or NKG2DCD3CD56 NK cells were significantly better restored in patients with HBeAg seroconversion. NK cell activating serum interleukin 15 (IL-15) was significantly increased during LdT treatment, especially in HBeAg seroconverters. LdT significantly enhanced expression of NKG2D and IL-15 in cultures of purified peripheral NK cells from treatment-naïve HBeAg-positive CHB patients.

CONCLUSIONS

Functional restoration of CD56 NK cells via upregulation of IL-15 and NKG2D is a novel activity of LdT and likely other antivirals, independent of its effect on HBV replication. This also demonstrates the importance of host immune restoration in controlling chronic HBV infection.