 If this blog seems like a Ginsu knife commercial – "Wait there's more!" - you're right and you're following along nicely. Besides macrophages, neutrophils, and the complement system that I've already described, there are several other key players involved in the innate immune system. One such is the natural killer cell, whose name seems to come straight out of the "Silence of the Lambs". It is so designated because it's similar to the killer T cell of the adaptive immune system, which I'll discuss later. But it kills naturally, that is, without making use of the adaptive immune system's exquisite specificity and diversity. Let me begin by offering an overview of the properties of this important player.
The third and fourth points are fascinating, new to me, and I elaborate on them below. Along the way, I'll cover some basic molecular biology that is worth learning about. Killer T cells seem to have arisen because organisms seem to face an intractable problem: How to they defend against viruses, entities that propagate inside of cells? The defenses that I've described so far, macrophages, neutrophils, and the complement system, largely attack invaders by detecting molecules on their outer membranes. Once a foreign microbe has penetrated this barrier it would seem to be invisible and therefore invulnerable. Natural killer cells get around this problem by employing an ingenuous strategy that makes use of a cellular component that most of are unaware: the major histocompatibility complex (often referred to as the MHC. I'll use that designation despite my dislike of initialisms because of the length of the name of the molecules to which it refers (it's awkward to keep typing such a long phrase) and because you'll come across it in many contexts. In particular, I'm going to come back to a discussion of the MHC in a later blog when I cover the adaptive immune system and will be sure to remind you of its meaning there.  Doesn't attack MHC I'll begin my discussion of the MHC with a fact that many of my students disbelieve ("fake news"?). We are not the same person that we were years ago, months ago, even minutes ago. That's because our innards are continually turning over. By that I mean, our cells are dying all the time and being replaced with new ones. Just to give one example, our red blood cells have an average lifetime of about four months. Given their numbers, that means that we're losing about 2 million cells a second. And, of course, they're being replaced at the same rate. Other cells are being recycled similarly, some even faster. Furthermore, what many people don't appreciate is that the internal components of all of our cells, in particular our proteins, are also constantly being destroyed and renewed. In fact, there is a specific organelle (it's called the proteosome in case you wanted to look it up and learn more about it) that is found in all cells that is responsible for chopping up our proteins so that new ones can take their place. What's this got to do with the MHC? Well, one form of the MHC, MHC I, is found in all cells with a nucleus (not human red blood cells because they've lost their nuclei during maturation). It has the responsibility for grabbing on to protein fragments from degraded proteins and displaying them on the cell surface. There's much more to this process, as you might imagine, but suffice it to say that cells with a MHC have on their surface a sampling of small bits of almost all their internal proteins, proteins that have been degraded but whose fragments have been captured by the MHC. These samples are less than 10 amino acids long and are waving about the outside of cells, advertising what's inside.  Attacks Natural killer cells have receptors on their surface that bind to the proteins of the MHC. Their response: They are inhibited and don't attack. Because normal cells bear an excess of these proteins, they're left alone. On the other hand, cells that that have been infected by a virus or have been stressed in other ways or are cancerous often have fewer MHC molecules on their surface. Moreover, stressed, injured, and cancerous cells may display a variety of other ligands on their surface, some of which may be recognized by the natural killers and which are excitatory and activating. When a natural killer cell encounters a cell bearing a decreased number of MHC molecules, it can attack. Whether it does so depends on the number of inhibitory MHC proteins on the surface of the probed cell versus the quantity of excitatory molecules. The take home lesson is that natural killer cells attack targets that are missing something, not because they bear a positive call to arms. The figures above illustrate the phenomenon.
Once a natural killer cell has targeted a cell for destruction, it signals it to commit suicide. Again, cell suicide (programmed cell death) may be a phenomenon of which most people are unaware. However, it has been recognized for decades. It's so old that I even learned about it as a graduate student. Rather then extend this posting past the patience of my readers, I'll forgo discussing the subject. Instead, for those interested, look up apoptosis in the usual references. Natural killer cells make use of a kind of borer to poke holes in the membrane of cells so that it can inject suicide signals into their quarry. Alternatively, some of their surface proteins may interact with proteins on the outer membrane of targeted cells that also signal programmed cell death. In both cases, the affected cell dies "neatly". In the words of Alberts et al., "The cell shrinks and condenses. The cytoskeleton collapses, the nuclear envelope disassembles, and the nuclear DNA breaks up into fragments. Most importantly, the cell surface is altered, displaying properties that cause the dying cell to be rapidly phagocytosed, either by a neighboring cell or by a macrophage" (Molecular Biology of the Cell, 4th edition, Alberts et al, free to read online). In addition, natural killer cells secrete cytokines that activate macrophages. All in all, the natural killer cell is a potent adversary for invading microbes. In the future, biologists may engineer it to take advantage of its properties and use them for medical purposes. In fact that's already happening. A paper published in late June, 2018 describes the how natural killer cells can be used to target cancer by engineering a unique receptor on it their surface. Here's the reference for those interested and willing to wade through the technical details. More about the innate immune system in the next post.
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