Natural Killer cells and Innate Immunity

Innate lymphoid cells

Within the ecosystem that is our body, NK cells are serious and highly selective predators: in just hours, they kill tumor or infected cells while sparing healthy cells.

In many laboratories around the world, scientists have combined their efforts to understand how these killers eliminate their targets and only their targets, even though they lack the highly selective antigen receptor of their close cousins, the T cells.Today we know not only how NK cells are controlled but also how they in turn control other agents of the immune system...

 

N for natural, K for killer, as its name suggests NK cells are primarily killer cells. With other cells of the innate immune system (neutrophils, monocytes, macrophages, dendritic cells and Tγδ lymphocytes) they patrol the body and mark cancer or infected cells. Once identified, the sick cell are destroyed in minutes by a mechanism known as cytotoxicity: the NK cells attack in packs by releasing substances that perforate the "skin" of their victims; this is death by cell lysis.

Meanwhile, the NK cells secrete cytokines (the "hormones" of the immune system) that stimulate and guide the response of other agents of innate immunity and lymphocytes of the adaptive immune system. Using their highly selective receptors (antibodies of B lymphocytes and T cell receptor), these latter cells identify antigens and remove the intruder while preserving the memory of the encounter, so that they can react more quickly when the pathogen or its close relatives renew the assault.

Lacking such a key recognition mechanism, how do the NK cells manage to distinguish a diseased cell from a healthy cell? The team was instrumental in solving this puzzle in the mid 90s.

"In the course of evolution NK cells have simply learned how to count"

"In order to distinguish the normal from the pathological, the NK cell has developed a sophisticated detection system," says Eric Vivier. "It is based on surface radar coupled to intracellular signaling pathways that transmit information to the cell nucleus so that it makes its decision: kill or not kill. These radars can be distinguished from activating and inhibitory receptors. The first spot the danger signals emitted by stressed cells and the only place the NK cell in mode 'extermination'." The latter detect self-molecules (called the major histocompatibility complex class I or MHC I) on all the healthy cells of each individual and deactivate the cytotoxic function of NK cell: the target is spared and the predator can then get back to patrol."

However, most of the time, the NK cell receives these antagonistic signals simultaneously. In this context how does it make its decision?

"During evolution, it has simply learned to count!" said Eric Vivier. "The NK cell sums the signals it receives: it spares healthy cells that send inhibitory signals and few or no activating signals, while it kills cancer cells or infected cells that not only deliver 'danger signals' but also become unable to send inhibitory protective signals. In sum, the NK cell works much like an ideal drug: effective and nontoxic."

Looking at the succession of molecular  "handshakes" that convey signals from the surface to the cell nucleus, the team made another unexpected discovery: near the transmembrane region of the activating receptors they found a small protein (KARAP/DAP12/Tyrobp), which carries a motif called ITAM (immunoreceptor tyrosine-based activation motif), without which the activation does not take place. At the same time, they revealed the existence of a pattern called ITIM (immunoreceptor tyrosine-based inhibition motif), on the inhibitory receptors (KIR in humans and Ly49 in mice). Like its counterpart activator, the ITIM motif alone conditions the response of the NK cell. In this case it blocks all of its mechanisms of activation.
These sequences are now considered "universal biological switches" that control the activity of many cell types.

The identification of molecules recognized by activating receptors is one of the new priorities of the team. "While the KIR receptor ligands are known, those of activating receptors remain to be discovered" reported Sophie Ugolini, project manager in the team.

Attacking inflammation, infection and cancer

Thus, by selectively killing their targets and interacting with their environment, NK cells can protect us from diseases by amplifying or reducing immune responses. Yet their role in vivo is still widely debated. "Idealy, we would need a mouse model in which we could selectively remove the NK cells 'at will'. This is exactly what we have done." reveals Eric Vivier. "It remains to confront it with viruses, bacteria and tumors to see how this mutant mouse will be able to resist these various attacks."

In reality, our NK cells are not always able to effectively fight the pathogens and cancers we face. Hence came the idea to build on these discoveries to boost their activity. With monoclonal antibodies several strategies are possible, especially removing the brake blocking their inhibitory receptors. This approach has been chosen by Innate Pharma, a company created in 1999 from the work of Alessandro Moretta, Professor at the University of Genoa, and Eric Vivier. These antibodies are currently evaluated clinically in cancer and inflammatory diseases.

Fron NK cells to innate lymphoid cells

In the course of recent work on the NKp46 receptor, one of the characteristic molecules of NK cells in humans and mice, the team was involved in the discovery of a new world of lymphocytes: that of the innate lymphoid cells (ILCs). These cells seem to be the innate equivalent of T lymphocytes. NK cells are natural members of this new category, and they express the NKp46 receptor at their surface, just like two subpopulations of ILCs (ILC1 and ILC3) present in the liver and intestine, respectively. The biology of these ILCs remains poorly understood and is one of the key focuses of the current activity of the team.