Liver molecules important for immunity

The hallmark of adaptive immunity is antigen presentation to T cells. This takes place through specialised receptors known as major histocompatibility complexes (MHC I or II). In addition, lipids get presented to natural killer T (NKT) cells through the CD1 family of receptors and this property is not restricted to antigen-presenting cells.

Emerging evidence indicates that the microsomal triglyceride transfer protein (MTP) is required for proper loading of lipids onto the CD1 receptor. Scientists on the EU-funded HEPATOCYTE MTP project wished to investigate this axis of antigen presentation in the liver. In this context, they generated transgenic mice lacking MTP specifically in hepatocytes and assessed antigen presentation.

MTP knockout hepatocytes exhibited a severe defect in the presentation of both endogenous and microbial-derived lipids to NKT cells. This was attributed to CD1 instability, causing defects in the tertiary structure of the receptor complex and an inability to bind antigen.

These findings were extrapolated to patients with abetalipoproteinemia, a metabolic disease caused by mutations in MTP. Dendritic cells from these patients show enhanced degradation of CD1 and lack of lipid presentation. Furthermore, researchers discovered that MTP regulated the homeostasis of liver-resident immune cells and was essential in the defence against Hepatitis B virus.

Overall, the key HEPATOCYTE MTP discovery was that MTP plays a central role in immune responses where lipid presentation is essential, such as in Hepatitis B infection. Given the millions of patients worldwide with chronic Hepatitis B, this result has significant implications for the development of therapeutic strategies for their treatment.