Tuesday, January 16, 2007

T cells

I'm seeing a number of interesting stories coming along about research into the immune system. Since this is a rather mysterious subject for most people, and it touches upon many other topics in health, medicine, and biotechnology, perhaps it's an appropriate time to start writing about it.

When I say "the immune system" I mean primarily the human immune system, although that has a lot in common with the immune systems of other mammals, and even other vertebrates.

In addition to obvious medical topics such as infectious diseases and auto-immune diseases, the immune system also has a lot of impact on cancer, diabetes, cardiovascular diseases, and other disorders. So let's get started, beginning with terminology, of which, unfortunately, there is a lot.

T cells are one type of immune system cell, which make up part of the class of "white blood cells". (To further confuse matters, "leukocyte" is a more technical synonym for "white blood cell".) More precisely, T cells belong to a subtype of white blood cells known as "lymphocytes", which are cells involved with the immune system. B cells are another very important kind of lymphocyte, but we'll focus mostly on the T cells here.

The immune system itself is considered to consist of two parts – the innate immune system and the adaptive immune system. The former consists of mechanisms that protect an organism from infection by invading parasites, without being very specific to kind. It is evolutionarily old and found even in plants. The latter part is evolutionarily newer, and seems to have first appeared in jawed vertebrates. It is capable of adapting to newly encountered pathogens and "remembering" how to stop them. Both B cells and T cells are part of the adaptive system. Another type of lymphocyte, the "natural killer" (or NK) cell, is part of the innate system.

T cells get their name from the organ known as the thymus, which is the location in which they mature. They provide cell-mediated immunity. (B cells provide a part of what is known as humoral immunity, which involve entities other than cells that assist with immunity, such as antibodies.) Some of the different types are cytotoxic T cells (also known – confusingly – as Tc, CD8+, or killer T cells), helper T cells (also known as Th or CD4+ cells), memory T cells, regulatory T cells (also known as suppressor T cells), and natural killer T cells (also known as NKT cells, and which should not be cofused with either Tc killer T cells or NK cells). You'll see various of these types discussed below. It's not necessary to memorize the types now. No snap quiz will be held.

The first research report we'll consider helps understand how killer T cells (Tc cells) attack and kill cancer cells. To begin with, all types of T cells have a molecule on their surface called a T cell receptor (TcR), but this occurs in highly variable forms. By definition, the Tc cell also has a molecule on its surface called CD8, which is a glycoprotein. Tumor cells (like any other cells) contain many large molecules on their surface, and a molecule which is unique for the particular kind of tumor cell is called an antigen. (Antigens occur in other contexts as well, such as in relation to viruses and bacteria.)

By virtue of the specific form of TcR on the surface of the Tc cell, the cell can interact only with other cells that present on their surface very specific parts (called epitopes) of specific antigens. When such an interaction successfully occurs and the Tc cell binds to the epitope, it is said to be "activated". This brings about important changes in the Tc cell. When this occurs, the Tc cell releases cytokines that cause it to proliferate, and also cell-killing toxins (cytotoxins) that induce cell death (apoptosis) in the tumor cell.

The first research report describes a technique for making actual movies of the T cell activity that occurs in destroying tumors. It also demonstrates how an experimental cancer vaccine can be used to activate Tc cells so that they can kill tumor cells.

Innovative Movies Show Real-time Immune-cell Activity Within Tumors
Using advanced new microscopy techniques in concert with sophisticated transgenic technologies, scientists at The Wistar Institute have for the first time created three-dimensional, time-lapse movies showing immune cells targeting cancer cells in live tumor tissues. In recorded experiments, immune cells called T cells can be seen actively migrating though tissues, making direct contact with tumor cells, and killing them.

In a nutshell, what the research showed was that mouse Tc cells would not kill tumors unless they had been activated with a vaccine based on the appropriate antigen. Further, once a Tc cell had destroyed its first tumor cell, the Tc cell began to migrate actively through the tumor to kill other tumor cells.

The second research report involves helper T cells (Th cells) instead of Tc cells. The two types of T cells are very similar except for several things. First, a Th cell contains a CD4 glycoprotein on its surface instead of CD8. The consequence of this is that a Th cell, once activated, binds to different kinds of cells, and in a different way, than a Tc cell does. Second, a Th cell does not produce cytotoxins, and so it cannot kill other cells directly. Instead a Th cell works indirectly through other immune system cells (primarily B cells, dendritic cells, and macrophages) to carry on immune system activities to clear an infection.

We need to explain a bit more about antigens and epitopes. An epitope (which is some fragment of an antigen) doesn't occur on a cell surface by itself, but instead is "presented" on the cell surface by a large molecule known as a major histocompatibility complex (MHC). Two types of MHC are important here: MHC class I and MHC class II. MHC class I molecules usually present epitopes that originate inside a cell, such as protein fragments specific to a cancer cell or a cell infected by a specific virus. Tc cells can bind only to MHC class I molecules combined with an epitope. MHC class II molecules usually present epitopes that originate outside a cell, such as fragments of proteins from a bacterial membrane. Also, MHC class II molecules generally occur only on special types of cells, called "professional" antigen presenting cells (which include B cells, macrophages, and dendritic cells). Essentially, the main purpose of such a cell is to carry epitopes that interact with other parts of the immune system.

Let's have an example of how some of this machinery works. Specifically, let's look at how the immune system deals with a flu virus. Suppose it is a virus that has recently mutated, so that the immune system has not encountered it before. It turns out that the immune system can handle the virus anyhow, but not very rapidly. A very important part of the immune system that deals with infections agents is known as an antibody. Antibodies are large proteins that consist of two parts. One part is the same for all antibodies of a particular class (and there are only five classes). The other part is highly variable, and can assume billions of different forms. Antibodies are manufactured in B cells, and there is a 1-1 correstpondence between B cells and antibodies: each type of antibody is manufactured by exactly one and only one type of B cell, depending on the precise DNA sequence in a part of the B cell's genome. The variability of B cell DNA is what gives the huge variety of antibodies.

The reason there are so many antibodies is that their function is to bind with (and only with) specific small parts of proteins – the epitopes – that occur in an antigen, such as a flu virus. The chances are very high that a flu virus will have in some fragment of one of its proteins a sequence that is the epitope some existing antibody binds to. When this happens, we say that the whole virus is an antigen for that antibody (and probably many others, for other epitopes).

When the new flu virus enters the body, however, it is quite possible that it does not immediately encounter any antibodies that bind to it. So the virus will go on to infect a cell somewhere. But cells are capable of killing at least some of the viruses that infect them. When this happens, some epitope from the virus is likely to be picked up and "presented" to the external environment of the cell by means of a class I MHC molecule, which exist in abundance on the cell membrane of most types of cells. Now, it turns out that the T cell receptor (TcR) molecule on the surface of a Tc cell is also highly variable, like an antibody, and will bind to a very limited number of epitopes. But eventually, a Tc cell that can bind will come along. When it does bind to the MHC molecule with an appropriate epitope it has never encountered before, the Tc cell is "activated". This results in two things (as we discussed earlier). First, the Tc produces cytotoxins that kill the infected cell. Second, it starts to proliferate rapidly, retaining its affinity for the epitope that activated it. Thereafter, the newly created Tc cells can spread throughout the body, killing other cells that are infected with the same virus.

There are two problems with this process, however. First, there will be a lot of dead cells as a result – not enough to do serious harm to the body, but not a good thing either. Second, the process takes a long time, allowing the virus to produce unpleasant and possibly harmful side effects, as anyone who's had a flu infection knows.

But there's good news too. There are many cells in the immune system called macrophages. They can swallow up foreign material like viruses – provided that this material has already been attached to some antibody. Otherwise, the macropage would go around swallowing up all sorts of things that need to be left alone. The main purpose of antibodies is to act as a flag to macrophages that the thing they're attached to needs to be destroyed. Now remember that there are also a few B cells around that manufacture antibodies that can bind to the virus via one of its epitopes. Although this will take some time, eventually the virus will get bound to an antibody, and somewhat later be swallowed up by a macrophage.

Something that is special about macrophages is that they can present epitopes on their surface using MHC molecules of class II. (B cells and dendritic cells are the other main kinds of cells that ordinarily have class II MHC molecules on their surface.) This will happen in the case of virus antigens that have been swallowed by the macrophage. The key thing is that the helper T cells (Th cells) are capable of binding to the MHC + epitope on the macrophage surface, provided the TcR of the Th cell matches the epitope. When that happens, the Th cell becomes activated, which will cause it to proliferate rapidly.

Now the B cells come into play again. They express some of the antibodies they produce on their cell surface, in addition to releasing them to the intercellular space. When one of these B cells encounters a virus having an epitope that binds to the antibody, the virus sticks to the cell, and is then swallowed and destroyed, just as with a macrophage. Of course, this happens a lot less than with macrophages, since the latter can trap a virus bound to any antibody, not only a very special one. But when it does occur, the epitopes of the virus are presented on the B cell surface via a class II MHC molecule. And so matching Th cells, which have been proliferating since being activated in an encounter with a macrophage, eventually come along. When one of those binds to the MHC + epitope of the B cell, it emits signal molecules (called cytokines) that cause the B cell to become activated. And that means that B cells that produce antibodies specific to the invading virus start to proliferate. From then on, things move more rapidly, until the virus infection is (hopefully) cleared.

Better yet, some of these virus-specific B cells hang around in the body, so that the next time the same virus is encountered, an immune system reaction gets going much more quickly. This is the reason that a person becomes immunized against a specific virus after the first exposure to it – if everything goes right. (Actually, there's also another way the infection can be "remembered", involving dendritic cells.)

This, of course, is how vaccines work. They include some form of the virus, or parts of it, that can't cause the full-blown disease, so that eventually the body will create a lot of B cells and antibodies specifically for the virus. (Neither the Th cells nor the Tc cells hang around for very long.) The problem is that this process doesn't work very well for a number of viruses, including HIV, which causes AIDS. This is why there hasn't yet been an effective AIDS vaccine developed.

But recently reported research has found a more efficient way to introduce virus epitopes into cells that are capable of including class II MHC molecules on their surface – such as epithelial (skin) cells. It's significantly more efficient, since it avoids the lengthy bootstrap process outlined above for generating lots of Th cells, because it doesn't rely on the need for existing antibodies in order to activate the Th cells by means of macrophages. See

Cellular Pathway Yields Potential New Weapon In Vaccine Arsenal
[The researchers] found that a surprising number of cells with MHC class II molecules on their surfaces used the autophagy pathway. In skin (epithelial) cells and two other types of immune cells (dendritic and B cells), 50 to 80 percent of the autophagosomes moved into the loading compartment for MHC class II molecules. “For types of cells that upregulate MHC class II upon inflammation — epithelial cells of infected organs, for instance — one could assume that they might actually use the autophagy pathway fairly frequently,” Münz says.

Then, to test the pathway’s effectiveness, the researchers targeted an influenza antigen directly to autophagosomes. They found that they were able to increase antigen presentation by MHC class II molecules, subsequently boosting helper T cell recognition of viral antigens.

The third piece of research we'll consider here involves one additional type of T cell not yet discussed: regulatory T cells (Treg for short). Such cells are thought to temporarily suppress the activity of the immune system, in order to avoid problems of overactivity. Such a regulatory mechanism can be important in controlling autoimmune diseases, preventing organ transplant rejection, or facilitating cancer immunotherapy.

Until recently, there was some doubt as to the existence of Treg cells as a distinct type of T cell, but the doubt is now overcome. The question now is, how to stimulate the production of Treg cells when they might be useful. As mentioned already, T cells mature in the thymus. During that process, early-stage T cells acquire the characteristics specific to Th, Tc, or other kinds of T cell, including Treg cells.

The researchers believe they have identified a process of "trans-conditioning" that makes the difference:

Scientists Show How Immune System Chooses Best Way To Fight Infection
"Our team has shown that a process known as 'trans-conditioning', which we knew to be involved in T cell development, actually has a profound influence on whether a T cell becomes an effector or a regulatory cell," explains Professor Adrian Hayday of King's College London. "This may be clinically significant; if we can find a way to influence this process, it may be possible to make the body produce effector T cells in a cancer patient or regulatory T cells in someone suffering from autoimmune disease, both of which are caused by the immune system malfunctioning."


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