Scientists have shown how an immune cell called the natural killer T cell mounts an early defense against hepatitis B virus infection by sensing modified fat molecules produced by infected liver cells. While most healthy adults clear the hepatitis B virus (HBV) on their own, some groups such as children are more vulnerable to chronic infection. The immune system has two main types of defenses against pathogens like HBV: innate immunity, which includes early cellular responders that attack invaders, and adaptive immunity, which involves activation of other cell types and the production over several days of specific antibodies against the invaders. Natural killer T (NKT) cells occupy a unique niche by responding early to pathogens as part of innate immunity, but then activating other cells that participate in both types of immune defense. Scientists set off to investigate what type of role these NKT cells might play in early defense against infection by HBV, with experiments in mice and in isolated liver cells. Because HBV does not naturally infect mouse liver cells, the scientists infected mice using a modified vector to deliver the HBV genome. As soon as 1 day after infection, NKT cells became activated in the liver, but not elsewhere. Using mice that were genetically modified to lack NKT cells and then infected with HBV, the researchers showed that activation of other immune cells typically stimulated by NKT cells was diminished, resulting in higher viral levels, fewer antibodies, and more hepatitis. In cell culture, they showed that mouse and human liver cells infected with HBV were necessary for the NKT cells to become active. When the liver cells became infected with HBV, they produced unique fat molecules (lipids) that signaled their infection to the NKT cells, which responded by producing chemicals that mount a full immune response and play a role in clearing the infection. These findings suggest that NKT cells contribute to early immunity against and clearance of HBV by sounding an alarm that alerts the immune system to the viral intruder. This research points to potential approaches to preventing and treating chronic HBV infection through targeting these cells.
Zeissig S, Murata K, Sweet L, et al. Hepatitis B virus-induced lipid alterations contribute to natural killer T cell-dependent protective immunity. Nat Med 18: 1060-1068, 2012.