Target cell recognition by natural killer cells

Natural killer (NK) cells make up about 5% of white blood cells. In addition to killing cancer cells, NK cells can recognize and kill cells that are infected with intracellular microorganisms, such as viruses and some types of parasites and bacteria. Intracellular infections can be difficult to prevent by vaccination, since many of the relevant microbes have developed strategies to hide from the immune system. Important examples in a global health perspective are tuberculosis, HIV and malaria. The current project aimed to identify the molecules that NK cells bind to on the surface of infected target cells, and the mechanisms that lead to activation of the NK cell killing machinery. The project has led to several findings that have initiated new experiments that are still ongoing. Molecular analysis has demonstrated that several NK cell receptors couple simultaneousy to the two most important signalling proteins in the cell membrane. This indicates that NK cells can be activated and kill infected cells based on a single "sick cell" indicator. Further work is ongoing to identify these "sick cell" surface molecules at the molecular level.

Tuberculosis causes a large number of deaths worldwide, as well as contributing to morbidity and reduced quality of life. Most prominent in economically underdeveloped countries, the disease is currently posing an increasing challenge to the western world due to incresed travel activity combined with the increasing occurrence of multiresistant strains of Mycobacterium tuberculosis. Currently available vaccination regimens have proven insufficient to eradicate the disease. Mycobacteria pose a special chall enge to the immune system. M. tuberculosis can reside for years inside host cells, before awaking to cause disease in immunocompromised individuals. In this latent state, humoral vaccines are not effective. Thus, new vaccination strategies that induce lon g-lasting, efficient cellular immunity are highly warranted. We have for many years studied natural killer (NK) cells, focusing on their ability to recognize cells that have undergone intracellular infection or malignant transformation. NK cells can recog nize and kill cells that are infected with parasites, virus or bacteria. Importantly, NK cells kill macrophages infected with M. tuberculosis. The present project is aimed at identifying the receptors that NK cells use to detect infection. Increased knowl edge about the role of NK cells in combating infection may provide a new approach to inducing protective immunity, given the recently demonstrated ability of NK cells to maintain immunological memory and form NK memory cells.