セミナー・研究会

Much of our knowledge of how the immune response is regulated in health and how is it manipulated in cancer. HCMV is one of the notable examples with this regard as it is known to be a master of immune evasion, encoding for many immuno-modulatory proteins. In addition it was recently discovered that herpes viruses (and also HCMV) also encode for microRNAs that could also potentially manipulate immune responses.

To ask whether the HCMV microRNAs could indeed manipulate the immune response we used bio-informatic tools and experimental approaches and identified the MICB gene as a candidate target of hcmv-miR-UL112. MICB is a stress-induced ligand of the natural killer (NK) cell activating receptor NKG2D and is critical for the NK cell killing of virus-infected cells and tumor cells. We showed that hcmv-miR-UL112 specifically down-regulates MICB expression during viral infection, leading to decreased binding of NKG2D and reduced killing by NK cells. We therefore revealed a novel microRNA-based immuno-evasion mechanism that is exploited by human cytomegalovirus to escape recognition by NK cells. These results were published in the Science Journal.

Following these discoveries we noticed that the site which is targeted by hcmv-miR-UL112 is conserved between different MICB alleles and a similar site is also located in another stress induced gene named MICA. We therefore next ask why is this site conserved. A simple solution for the host to avoid MICB downregulation would be to mutate this site. We hypothesized that this site is conserved because it is targeted by endogenous cellular-microRNAs and is therefore indispensable for host and is protected from manipulations. Indeed, we identify the candidate cellular microRNAs and demonstrated that these microRNAs maintain expression of MICA and MICB protein under a certain threshold under normal conditions and facilitate acute upregulation of MICA and MICB during cellular stress. We also demonstrated that tumor cells such as lymphoma and leukemia overexpress these cellular microRNAs to avoid immune cell attack. These results were recently published in the Nature Immunology Journal. Thus, through the identification of the function of a viral microRNA, we discover a novel mode of regulation that protect normal cells from self destruction and demonstrated a new tumor immuno-evasion strategy.

Finally, we have demonstrated the function of only one of the HCMV viral microRNAs. The function of the other ten is still unknown. We therefore cloned all HCMV microRNAs and we are currently examining the general function of these microRNAs with regard to immune evasion and the life cycle of the virus.