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To celebrate Day of Immunology on 29 April 2020, we asked some of our scientists to summarise their research advances into the immune system. Each day this week we’ll be delving into a different area of this research, beginning with our immune system’s internal defences.

Written Catriona Nguyen-Roberston, PhD Student, Doherty Insitute

Natural killer cells are the immune’s system intrinsic defences against infection and cancer. They kill cells infected by viruses and tumour cells, catching them in the early stages. Natural killer cells also produce a large number of alarm signals that recruit other immune cells to join the fight. While on patrol, natural killer cells constantly interact with cells of the body, receiving signals via activating and inhibiting receptors on their surface.

Whether or not a natural killer cell goes in for the kill is dependent on the balance of the “go” and “stop” signals it receives. Most normal, healthy cells provide a “stop” signal, detected via inhibitory receptors, to switch of the natural killer cell and prevent it from killing. Cancer cells and infected cells often lose this “stop” signal, leaving them vulnerable to killing.

Some of the main activating receptors on natural killer cells are called natural cytotoxicity receptors (NCRs), so named because they trigger the release of cytotoxic molecules into target cells to kill them. NCRs can also be found on other types of immune cells, endowing them with “natural killer-like” anti-tumour activity. Many molecules made by both our own cells and pathogens, such as viruses and bacteria, provide “go” signals to these receptors. These “go” signals can accumulate on the surface of tumour or virus-infected cells, marking themselves as targets for death.

Given the central role of natural killer cells in combating infectious disease, some pathogens, such as herpesviruses, have evolved mechanisms to avoid NCR recognition. When they infect cells, they remain hidden by establishing a latent infection (not actively taking over the host cell) and limiting the number of molecules produced that can activate NCRs, thus impairing natural killer cell recognition of infected cells.

Researchers at the Doherty Institute, led by Dr Alexander Barrow, reviewed how NCRs regulate the functions of natural killer cells and natural killer-like cells to understand how they contribute to health and disease. NCRs can be manipulated in novel immunotherapies, particularly for enhanced tumour surveillance to monitor and detect cancers. But NCRs can also be destructive in the context of some diseases, such as allergies and autoimmunity. It is therefore imperative to get these “go” and “stop” signals right for the snipers of our immune system.

A paper on this research was published in Frontiers in Immunology.