To Learn Immunology Well: Section 3

  • Categories:Learn about the Vaccines
  • Author:AKATSUKI
  • Origin:WeChat official account -- Quick View of Pharmacy
  • Time of issue:2021-02-03
  • Views:0

(Summary description)

To Learn Immunology Well: Section 3

(Summary description)

  • Categories:Learn about the Vaccines
  • Author:AKATSUKI
  • Origin:WeChat official account -- Quick View of Pharmacy
  • Time of issue:2021-02-03
  • Views:0

▉ Introduction

In the previous section, we introduced the role of B cells and antibodies in the adaptive immune system, and recognized that they are an integral part of the immune system against foreign invaders. Although antibodies can tag viruses for phagocytic ingestion, and can help keep viruses from infecting cells, there is a weakness in the antibody defense against viruses: Once a virus gets into a cell, antibodies can’t get to it, so the virus is safe to make thousands of copies of itself. Nature recognised this problem very early and found a corresponding solution. Another member of the adaptive immune system was created: the famous killer T cell.

▉ T cell

The importance of T cells is suggested by the fact that an adult human has about 300 billion of them. T cells are very similar to B cells in appearance. In fact, under an ordinary microscope, an immunologist can't tell them apart. Like B cells, T cells are produced in the bone marrow, and on their surface they display antibody-like molecules called T cell receptors (TCRs). Like the B cell's receptors (the antibody molecules attached to its surface), TCRs also are made by a mix-and-match, modular design strategy. As a result, TCRs are about as diverse as BCRs. T cells also employ the principle of clonal selection: When a T cell's receptors bind to their cognate antigen, the T cell proliferates to build up a clone of T cells with the same specificity. This proliferation stage takes about a week to complete, so just like the antibody response, the T cell response is slow and specific.


Figure 1: T cell


Although they are similar in many ways, there are also important differences between B cells and T cells. Whereas B cells mature in the bone marrow, T cells mature in the thymus. Further, whereas B cells make antibodies that can recognize any organic molecule, T cells specialize in recognizing protein antigens. In addition, a B cell can secrete its receptors in the form of antibodies, but a T cell's receptors remain tightly glued to its surface. Perhaps most importantly, a B cell can recognize an antigen "by itself," whereas a T cell is more like an elderly English gentleman who will only recognize an antigen if it is "properly presented" by another cell.


Figure 2


There are actually three main types of T cells: killer T cells, helper T cells, and regulatory T cells. The killer T cell is a potent weapon that can destroy virus-infected cells. Indeed, by recognizing and killing these cells, the killder T cells solve the "hiding virus" problem – the weakness mentioned in the previous section about the antibody defense against viruses. The way a killer T cell destroys virus-infected cells is by making contact with its target and then triggering the cell to commit suicide! This "assisted suicide" is an effective way to deal with viruses that have infected cells, because when a virus-infected cell dies, the viruses within the cell die also.


The second type of T cell is the helper T cell (Th cell). As you will see, this cell serves as the quarterback of the immune system team. It directs the action by secreting chemical messengers (cytokines) that have dramatic effects on other immune system cells. These cytokines have names like interleukin 2 (IL-2) and interferon gamma (IFN-γ), and we will discuss what they do in later sections. For now, it is only important to realize that helper T cells are basically cytokine factories.


The third type of T cell is the regulatory T cell (Treg), which appears to be a bit mysterious at present. The role of this type of T cell is to keep the immune system from overreacting, but how Tregs perform their functions has not been fully understood.


▉ Antigen presentation

It turns out that special proteins called major histocompatibility complex (MHC)proteins do the "presenting," and that T cells use their receptors to "view" this presented antigen. "histo" means tissue, and these major histocompatibility proteins, in addition to being presentation molecules, are also involved in the rejection of transplanted organs. In fact, when you hear that someone is waiting for a "matched" kidney, it's the MHC molecules of the donor and the recipient that the transplant surgeon is trying to match.


There are two types of MHC molecules, called class I and class II. Class I MHC molecules are found in varying amounts on the surface of most cells in the body. Class I MHC molecules function as "billboards," which inform killer T cells about what is going on inside these cells. For example, when a human cell is infected by a virus, fragments of viral proteins called peptides are loaded onto class I MHC molecules, and transported to the surface of the infected cell. By inspecting these protein fragments displayed by class I MHC molecules, killer T cells can use their receptors to "look into" the cell to discover that it has been infected and that it should be destroyed.


Class II MHC molecules also function as billboards, but this display is intended for the enlightenment of helper T cells. Only certain cells in the body make class II MHC molecules, and these are called antigen presenting cells (APCs). Macrophages, for example, are excellent antigen presenting cells. During a bacterial infection, a macrophage will "eat" bacteria, and will load fragments of ingested bacterial proteins onto class II MHC molecules for display on the surface of the macrophage in the form of complexes. Then, using their T cell receptors, helper T cells can scan the macrophage's class II MHC billboards for news of the bacterial infection. In summary, class I MHC molecules alert killer T cells when something isn't right inside a cell, and class II MHC molecules displayed on APCs inform helper T cells that problems exist outside of cells.


Figure 3: Billboard


Although a class I MHC molecule is made up of one long chain (the heavy chain) plus a short chain (β2-microglobulin), and a class II MHC molecule has two long chains (α and β), you'll notice that these molecules are rather similar in appearance.


Figure 4: MHC molecules


It's hard to visualize the real shapes of molecules from drawings like this, so I'd show you a few pictures that may make this more real to you. Here's what an empty MHC molecule might look like from the viewpoint of the T cell receptor. Right away you see the groove into which the protein fragment would fit.


Figure 5: Empty MHC molecule


The picture below shows a fully-loaded, class I molecule. I can tell it's a class I MHC molecule because the peptide is contained nicely within the groove. It turns out that the ends of the groove of a class I molecule are closed, so a protein fragment must be about nine amino acids in length to fit in properly. Class II MHC molecules are slightly different.


Figure 6: Class I MHC molecule


Here you see that the peptide overflows the groove. This works fine for class II, because the ends of the groove are open, so protein fragments as large as about 20 amino acids fit nicely.


Figure 7: Class II MHC molecule


So MHC molecules resemble buns, and the protein fragments they present resemble wieners. And if you imagine that the cells in our bodies have hot dogs on their surfaces, you won't be far wrong about antigen presentation.


▉ Activation of the adaptive immune system

Because B and T cells are such potent weapons, there is a requirement that cells of the adaptive immune system must be activated before they can function. Collectively, B and T cells are called lymphocytes, and how they are activated is one of the key issues in immunology. To introduce this concept, we need to first understand how helper T cells are activated.


The first step in the activation of a helper T cell is recognition of its cognate antigen displayed by class II MHC molecules on the surface of an antigen presenting cell. But seeing its cognate antigen on that billboard isn't enough – a second signal or "key" also is required for activation. This second signal is non-specific (it's the same for any antigen), and it involves a protein (B7 in this drawing) on the surface of an antigen presenting cell that plugs into its receptor (CD28 in this drawing) on the surface of the helper T cell.


Figure 8: Activation of a helper T cell


You see an example of this kind of two-key system when you visit your safe deposit box. You bring with you a key that is specific for your box – it won't fit any other. The bank teller provides a second, non-specific key that will fit all the boxes. Only when both keys are inserted into the locks on your box can it be opened. Your specific key alone won't do it, and the teller's non-specific key alone won't either. You need both. Now, why do you suppose helper T cells and other cells of the adaptive immune system require two keys for activation? For safety, of course – just like your bank box. These cells are powerful weapons that must only be activated at the appropriate time and place.


Figure 9: Two-key system


Once a helper T cell has been activated by this two-key system, it proliferates to build up a clone composed of many helper T cells whose receptors recognize the same antigen. These helper cells then mature into cells that can produce the cytokines needed to direct the activities of the immune system. B cells and killer T cells also require two-key systems for their activation, and we'll talk about them in another section.



▉ The secondary lymphoid organs

If you've been thinking about how the adaptive immune system might get turned on during an attack, you've probably begun to wonder whether this could ever happen. After all, there are only between 100 and 1,000 T cells that will have TCRs specific for a given invader, and for these T cells to be activated, they must come in contact with an antigen presenting cell that has "seen" that invader. Given that these T cells and APCs are spread all over the body, it would seem very unlikely that this would happen before an invasion got completely out of hand. Fortunately, to make this work with reasonable probability, the immune system includes "meeting places" –  the secondary lymphoid organs. The best known secondary lymphoid organ is the lymph node. You may not be familiar with the lymphatic system, so I'd better say a few words about it.


In your home, you have two plumbing systems. The first supplies the water that comes out of your faucets. This is a pressurized system, with the pressure being provided by a pump. You have another plumbing system that includes the drains in your sinks, showers, and toilets. This second system is not under pressure – the water just flows down the drain and out into the sewer. The two systems are connected in the sense that eventually the wastewater is recycled and used again.


Figure 10


The plumbing in a human is very much like this. We have a pressurized system (the cardiovascular system) in which blood is pumped around the body by the heart. But we also have another plumbing system – the lymphatic system. This system is not under pressure, and it drains the fluid (lymph) that leaks out of our blood vessels into our tissues. Without this system, our tissues would fill up with fluid and we'd look like the Pillsbury Doughboy. Fortunately, lymph is collected from the tissues of our lower body into lymphatic vessels, and is transported by these vessels, under the influence of muscular contraction, through a series of one-way valves to the upper torso. This lymph, plus lymph from the left side of the upper torso, is collected into the thoracic duct and emptied into the left subclavian vein to be recycled back into the blood. Likewise, lymph from the right side of the upper body is collected into the right lymphatic duct and is emptied into the right subclavian vein. From this diagram, you can see that as the lymph winds its way back to be reunited with the blood, it passes through a series of way stations – the lymph nodes.


Figure 11: Secondary lymphoid organs


In a human, there are about 500 lymph nodes, ranging in size from very small to almost as big as a Brussels sprout. Most are arrayed in "chains" that are connected by lymphatic vessels. Invaders such as bacteria and viruses are carried by the lymph to nearby nodes, and antigen presenting cells that have picked up foreign antigens in the tissues travel to lymph nodes to present their cargo. Meanwhile, B cells and T cells circulate from node to node, looking for the antigens for which they are "fated." So lymph nodes really function as "dating bars" – places where T cells, B cells, APCs, and antigen all gather for the purpose of communication and activation. Bringing these cells and antigens together within the small volume of a lymph node greatly increases the probability that they will interact and efficiently activate the adaptive immune system.


▉ Immunological memory

After B and T cells have been activated, have proliferated to build up clones of cells with identical antigen specificities, and have vanquished the enemy, most of them die off. This is a good thing, because we wouldn't want our immune systems to fill up with old B and T cells. On the other hand, it would be nice if some of these experienced B and T cells would stick around, just in case we are exposed to the same invaders again. That way, the adaptive immune system wouldn't have to start from scratch. And that's just the way it works. These "leftover" B and T cells are called memory cells. In addition to being more numerous than the original, inexperienced B and T cells, memory cells are easier to activate. As a result of this immunological memory, during a second attack, the adaptive system usually can spring into action so quickly that you never even experience any symptoms.


▉ Tolerance of self

As I mentioned earlier, B cell receptors and T cell receptors are so diverse that they should be able to recognize any invader. However, this diversity poses a potential problem: If B and T cell receptors are this diverse, many of them are certain to recognize our own "self" molecules e.g., the molecules that make up our cells, or proteins like insulin that circulate in our blood. If this were to happen, our adaptive immune system might attack our own bodies, and we could die from autoimmune disease. Fortunately, nature has developed a way to teach B cells and T cells to distinguish ourselves from dangerous "invaders". Although immunologists still don't understand the details of the tests used to eliminate self-reactive B and T cells, this testing is sufficiently rigorous that autoimmune disease is relatively rare.


▉ A comparison of the innate immune system and adaptive immune systems

Now that you have met some of the main players, I want to emphasize the differences between the innate and adaptive immune system "teams." Understanding how they differ is crucial to understanding how the immune system works.


Imagine that you are in the middle of town and someone steals your shoes. You look around for a store where you can buy another pair. The first store you see has shoes of every style, color, and size, and the salesperson is able to fit you in exactly the shoes you need. However, when it comes time to pay, you are told that you must wait a week or two to get your shoes – they will have to be custom-made for you, and that will take a while. But you need shoes right now! So they send you across the street to another shoe store .This store does stock shoes in the common sizes that fit most people. Consequently, you can buy a pair of shoes from the second store that will tide you over until your custom shoes are made for you.


This is very similar to the way the innate and adaptive immune systems work. The players of the innate system (such as the macrophage) are already in place, and are ready to defend against a relatively small attack by invaders we are likely to meet on a day-to-day basis. Indeed, in many instances, the innate system is so effective and so fast that the adaptive immune system never even kicks in. In other cases, the innate system may be insufficient to deal with an invasion, and the adaptive system will need to be mobilized. This takes time, however, because the B and T cells of the adaptive system must be custom-made through the process of clonal selection and proliferation. Consequently, while these "designer cells" are being produced, the innate immune system must do its best to hold the invaders at bay.


Figure 12


▉ Summary

This section mainly introduces T cells and the process of antigen presentation in the adaptive immune system as well as the activation of the adaptive immune system. Such a cell-mediated immune response well solves the trouble of intracellular viruses with which antibodies cannot handle. After three sessions, you should have a general understanding of the immune system. From the next section, we will go further and learn more about the details of the work of the immune system, thereby deepening the understanding of the immune system. Please stay tuned! To be continued!



Figure 1:

Figure 4, 5, 6, 7, 8, 11: How the Immune System Works

Figure 2,3,9,10,12:

Bibliography: How the Immune System Works


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