The Human Immune System – Part 5

How your immune system catalogues a library of antigens, and how T Cells work.

Continuing this essay series on the human immune system, this essay explores how your immune system catalogues a library of antigens, and how T Cells work.  As Philipp Dettmer writes in his book Immune: A Journey into the Mysterious System That Keeps You Alive:

How can your slow continent of flesh adapt to create specific defenses for each of the millions of different microorganisms and the millions more that don’t even exist yet? The answer is as simple as it is baffling: The immune system does not so much adapt to new invaders as it already was adapted when you were born. It comes preinstalled with hundreds of millions of different immune cells— a few for every possible threat that you could possibly encounter in this universe. Right now you have at least one cell inside you that is a specific weapon against the Black Death, any variant of the flu, the coronavirus, and the first pathogenic bacteria that will emerge in a city on Mars in one hundred years. You are ready for every possible microorganism in this universe. In the language of immunology, a protein piece that is recognized by the immune system is called an antigen. There are hundreds of millions of possible antigens that your Innate Immune System doesn’t recognize and through the magic of evolution there will always be new ones created in the future. There are hundreds of millions of potential antigens, hundreds of millions of different possible proteins. To solve this problem your adaptive immune system has an ingenious solution. In your body right now, there is at least one immune cell that has a receptor that can recognize one of the many millions of different antigens that can exist in the universe. Let that sink in for a moment. It is sort of easy to brush over this fact without giving it the appropriate amount of wonder … [Y]our adaptive immune cells takes gene segments and randomly combines them, then it does the same again, and then it randomly pulls out or adds in parts, to create billions of different receptors. They have three different groups of gene fragments. They randomly choose one from each group and put them together. Then they do this again, but with fewer fragments … And then when they are done, they randomly remove or add in parts. This way your adaptive immune cells create at least hundreds of millions of unique receptors. Each of them is an antigen from a microorganism that could invade your body. But there is a catch— this ingenious way to create such stunning variety makes your adaptive immune cells critically dangerous to you. Because what is stopping them from developing receptors that are able to recognize self, the parts of your own body? Well, their education is. So let us finally talk about your most important organ you have never heard of. Your Thymus is absolutely crucial for your survival and, in a way, will decide at what age you will die, so you might think that it would be as well- known as the liver, lungs, or heart. But weirdly enough, most people are not even aware that they have this organ … [I]t is one of your most important immune cell universities … Some of your most powerful, crucial adaptive immune cells are educated and trained here: T Cells.  T Cells got their name from the Thymus, because they go to school here.

Dettmer explains how T Cells work:

[T Cells do] things, from orchestrating other immune cells, to being antivirus superweapons, to killing cancer cells. We will talk about this amazing cell and all the mind-blowing things it does in more detail later, for now just remember: Without T Cells you are quite dead— they may be the most important Adaptive Immune Cell you have. But before they can fight for you, they need to pass the horribly dangerous curriculum in the Thymus. Failing a test here doesn’t mean bad grades. Failing here means death … [E]ach individual T Cell is born with ONE specific type of receptor, able to recognize ONE specific antigen. But there is a vital flaw: With so many different receptors there are guaranteed to be a large number of T Cells with receptors that are able to connect to proteins from your own cells. This is not a theoretical danger, but the cause of a number of very real and serious diseases that millions of people are suffering from right now called autoimmune diseases. For example, let’s say a T Cell receptor can connect to a protein on the surface of a skin cell, it would not understand that it is connecting to a friend. It would just try to kill it. Or worse, since there are quite a lot of skin cells in the human body, it would think a large attack was going on with enemies everywhere, and alert the rest of the immune system to go into attack mode, and cause inflammation and all sorts of chaos. In a nutshell, an autoimmune disease is your adaptive immune system thinking that your own cells are enemies, that they are other. It is no hyperbole to say that this is a critical danger to your survival … [Your] body takes this issue extremely seriously and came up with the Murder University of the Thymus to address it. After a fresh and young T Cell has been born it travels to the university and begins its training, which consists of three steps, or better, three tests: The first test is basically just making sure the T Cells have the ability to make working T Cell receptors. If this were a regular school, this would be the teachers checking if the students have all their notebooks and required reading material with them … The second test is called positive selection: Here the teacher cells check if the T Cells are really good at recognizing the receptors of the cells they will need to work with. Imagine this part as if the teacher is checking if the pens the students brought are all full of ink and that the workbooks are in fine condition. After the two first hurdles have been taken the last and most important test waits for our T Cell students: Negative selection. And this might be the hardest test of all. The final exam is simply: Can the T Cell recognize self? Can its receptor connect to the main proteins inside the body? The proteins that make you, you? The only acceptable answer is “No, not at all.” So in the final exam the T Cells are presented with all sorts of protein combinations that are used by the cells of your body. The way this happens is pretty fascinating by the way— the teacher cells in the Thymus that do the testing have a special license to make all sorts of special proteins that usually are made only in organs like the heart, pancreas, or the liver and also hormones, like insulin for example. This way they can show the T Cell all kinds of proteins that are marked as “self.” If a T Cell is able to recognize any of these self- proteins, they are taken out back and shot in the head immediately … Roughly ten to twenty million T cells will leave your Thymus today. They represent the successful 2% of survivors. These survivors are so diverse that you end up with at least one T Cell that can recognize basically every possible enemy that the universe could throw at you … Unfortunately your Murder University is already in the process of shutting down. Your Thymus basically begins shrinking and withering away when you are a small child. A process that is sped up once you reach puberty. Every year you are alive more and more Thymus cells turn into fat cells or just worthless tissue. The university closes more and more departments and gets worse as you age, until around the ripe age of eighty- five, your T Cell university closes its gates for good. There are other places in the body where T Cells can be educated, but for the most part from this point forward your immune system is more limited than before. Because once your Thymus is gone, you have to get by with the T Cells you have trained up to this point. The absence of the immune cell university is one of the most important reasons why seniors are much weaker and more susceptible to infectious diseases and cancer than younger people. Why is that so? Well, the problem is nature does not care about us once we are no longer making babies, so there is just no real evolutionary pressure to keep us around in older age … Some of the more promising efforts of the life- extension community are in finding ways to delay the shrinkage or even regrow Thymus tissue … [I]f you are reasonably young while reading this, there might be a chance that by the age you retire there will be drugs or treatments to regenerate your Thymus! … [W]hile your adaptive immune system has billions of different cells, each with a receptor for every possible enemy, it only has maybe ten to a dozen cells with each unique receptor. Which makes sense if you think about it. If you had millions of cells for every single one of the hundreds of millions of possible different pathogens, you would consist of quadrillions of immune cells and nothing else. On the one hand you would probably never get sick because you were so well prepared. But then again you would just be a puddle of slime … [N]ature found a much better and extremely elegant way to solve this conundrum. When an infection occurs, your immune system determines which specific defense is needed and how much of it. The adaptive immune system works together with the Innate Immune System to find the few cells that have the right receptors for this specific invasion, locate them among billions of others in your huge body, and then rapidly produce more of these cells. Not only does this method enable you to get by with just a few cells for each possible enemy, it also makes sure that the immune system does not overproduce weapons and waste resources— which is good because the immune system is already a pretty energy-intensive system as is. How does it do this? By preparing a presentation.

Dettmer then describes the fascinating process by which Dendritic Cells transmit information about pathogens to T Cells:

Dendritic Cells literally disassemble pathogens into antigen- sized pieces and pack them into special contraptions on their membranes. On the human scale this would mean killing an enemy soldier and then covering yourself with bits and pieces of their muscles, organs, and bones so others could examine them. Covered in guts, the Dendritic Cell then travels through the lymphatic system to present them to the Adaptive Immune System, or more precisely, to Helper T Cells. You might still think the fact that this principle actually works is a bit crazy. After all, what are the odds that a Dendritic Cell carrying a specific antigen, will find exactly the right T Cell that has the matching receptor for a specific enemy? What are the odds of picking a random puzzle piece out of millions and finding the one cell out of billions that carries the matching puzzle piece that just so happens to fit perfectly into it? Well for one, it is not just a single Dendritic Cell, in an infection at least dozens will make the trip. And on top of that the system is helped by fast travel. T Cells traverse the whole of your lymphatic superhighway once per day … [T]he Clonal Selection Theory[‘s] discovery won a Nobel Prize and it is one of the most crucial principles of how your immune system works. The theory basically goes like this: Your activated T Cell leaves the Dendritic Cell that activated it behind and wanders to a different part of the Lymph Node City where it begins the process of cloning itself. It divides over and over again, multiplying as fast as it can. One activated Helper T Cell becomes two, two become four, four become eight, and so on. Within hours there are thousands of them. (And because each of the clones has the same unique T Cell receptor like the first Helper T Cell that got activated, your immune system now has thousands of cells with this unique receptor that is an exact fit to the enemy.)

What follows is an astonishing chain of evolutionary processes in which T and B Cells are activated through different paths and then meet each other.  As Dettmer writes:

B Cells are large, blob-like fellows that share a few characteristics and properties with T Cells, namely that they originate in the bone marrow and that they have to undergo the same brutal and deadly education—only it doesn’t happen in the Thymus but directly in the bone marrow. Just like their T Cell buddies, all your B Cells combined come with at least hundreds of millions to billions of different receptors for millions of different antigens. And just like T Cells, every single individual B Cell has one specific receptor that is able to recognize one specific antigen. What makes B Cells special, and very dangerous for friends and foes, is that they produce the most potent and specialized weapon the immune system has at its disposal: Antibodies. Antibodies are weird things and pretty complex and fascinating, so we will brush over them here and discuss them in the detail they deserve a bit later, but in a nutshell—Antibodies are basically B Cell receptors … Remember lymph is this weird, slightly disgusting fluid that is constantly collected from all the tissues in your body. And in the case of an infection, the lymph is carrying all the dead and dismantled bacteria with it, a lot of them covered in complement proteins. This way the lymph flowing through you is a liquid information carrier. And this information is headed towards the next immune system base, the megacities and intelligence centers of the lymph nodes. Once it arrives here it is drained through the B Cell area where thousands of virgin B Cells hang out. The B Cells get right in the middle of the stream of fluid information and let the lymph flow around them and their B Cell receptors, which sift and explore all the antigens and detritus coming from your tissue. The virgin B Cells look specifically for antigens they can connect to with their special and unique B Cell receptors. They are fishing for the one antigen they can connect to, so they know they can activate! … B Cells can pick up large antigen chunks … directly from the lymph that flows through your lymph nodes. OK, so we learned two things now: Virgin B Cells sit in your lymph nodes, where they bathe in lymph and take in all the antigens that are transported through the area from the closest battlefield. Their B Cell Receptors can just grab big chunks of antigens directly from the lymph and this way B Cells can get activated … Your B Cell that was properly activated through the two- factor authentication now changes. It has waited its whole life for this moment. It begins to swell, to almost double its size, and transforms into its final form: the Plasma Cell. The Plasma Cell now begins producing antibodies for real. It can release up to 2,000 antibodies per second that saturate the lymph and blood and the fluids between your tissue. Like the Soviet rocket batteries in World War II that could send a never- ending barrage of missiles on enemy positions, antibodies are made in the millions and become every enemy’s worst nightmare, from bacteria to viruses or parasites … Can you appreciate the level of sophistication that is happening here? How insane it is to make billions of individual T and B Cells, activate them individually through different paths, and then expect them to meet each other? Evolution and time are truly incredible at crafting insanely complex and elegant mechanisms. If this sequence of events happens, the last and most powerful stage of the Adaptive Immune System finally starts up in earnest and awakens. Now all the conditions the immune system could ever ask for have been fulfilled. It now knows for sure that there are a lot of enemies active inside the body … The immune system evolved this way because it is better to have some working weapons as quickly as possible than perfect weapons after all the damage is already done. But this also weakens your immune defense. As we said, on the level of proteins, shape is everything, and having Antibodies with a really good shape that fits really well on an antigen is an incredible advantage that can mean the difference between life and death. And your immune system wants it all, a quick response and then a perfect defense. So your immune system came up with a way to produce OK-ish Antibodies as fast as possible but also with an ingenious system to fine- tune and improve the Antibodies, so they become actually perfect weapons against the antigen … This mechanism makes the Adaptive Immune System actually adapt to the enemy in real time. We asked before how you could keep up with the billions of different enemies that are also able to change themselves. This is one way. A system that can replicate very quickly, that has a defined target and can adapt to it fast, that fine- tunes and improves its weapons until they are perfect. What a beautiful and ingenious solution that shows that the Adaptive Immune System really deserves its name— it truly can beat microbes at their own game.

In the next essay in this series, we’ll explore the unique threat posed to us by viruses.