15-22 There are several types of T cells, but all mature in the thymus

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• Mature T cells are classified by their role the immune system. T helper cells help regulate the immune system. Cytotoxic T cells attack cells that have been infected or are displaying odd antigens.
• In the thymus, T cells are exposed to various self-antigens. If they react, the T cell is allowed to die, if they do not, then the T cell survives.
• Not all host-reactive T cells are eliminated by their education in the thymus, but these self-reactive T cells are kept under control by clonal anergy, active suppression and sequestering

The response T cells have to the presentation of antigens by the MHC molecules on other cells depends upon the type of T cell. Two major subpopulations of T cells differ from one another by the type of surface protein that they display. Mature T cells contain either the CD4 protein or the CD8 protein on their surface. Cells that contain CD4 are further subdivided into three subsets: T helper 1 cells (T_H1); T helper 2 cells (T_H2); and T_HO cells. T_H1 cells participate in cell-mediated immunity and are responsible for recruiting and regulating nonspecific immune cells such as phagocytes. They also help to regulate the steps of inflammation and thus are called T inflammatory cells. T_H2 cells serve to activate B cells to differentiate and produce antibody. In most cases, only small amounts of antibody are produced by B cells on their own and T_H2 cells are necessary to get full activation of the B cells and large amounts of antibody production. Not much is known about T_HO cells except that they are a distinct class of T helper cells with their own set of cytokines that they secrete; these cells may differentiate into mature T_H1 or T_H2 cells.

The second group of T cells, those with CD8 on their surface, are called T cytotoxic (T_c) cells, also known as cytotoxic T lymphocytes. Presentation of an antigen by a host cell to a T_c cell causes its activation and it then proceeds to attack and kill the cell that presented the antigen. T_c cells can be thought of as sentries that follow prescribed routes, patrolling our bodies looking for cells displaying odd antigens in their MHC molecules. They also respond to cells that raise the alarm, sent out in the form of an inflammatory response. When found, T_c cells destroy these cells.

T cell maturation and tolerance

T cells originate from bone marrow stem cells in an immature form. Immature T cells can collectively attack a wide range of antigens, including antigens on our own cells. These cells must be selected to only react against non-self antigens and this education takes place in the thymus as shown in Figure 15-22.

At this point, the education of the T cells begins. Remarkably, immature T cells are initially programmed to die and only through intervention by the thymus do they survive. During their time in the thymus, T cells are exposed to various self-antigens. If they react to the antigen, the T cell is encouraged to carry out its cellular program and die. In fact, the thymus is something of a graveyard for T cells with only about 10% surviving the treatment (some education system!). It may seem more logical to set up the system so that the thymus kills bad T cells, but if you think about it, preprogrammed death is actually safer. If a damaging immature T cell somehow escapes education, it will still die since an educating cell did not tell it to live. In this fashion, the body averts many potential autoimmune reactions. Those T cells that do survive are assumed to be protective against non-self antigens and are released into the bloodstream. These mature T cells then roam throughout their body to fulfill their functions.

Note that B cells undergo a similar type of culling process as T cells to remove self-reactive antibodies, but this process takes place in the bone marrow and not in the thymus. Since the process is very similar to that described for T cells, we will not cover it in detail. Briefly, developing B cells are presented with self-antigens. Reaction between the B cell receptor (remember this is IgD or IgM on the surface of the B cell) and the antigen causes the B cell to die. In this way, the body only produces antibodies to foreign antigens.

The above mechanism is one way the body creates tolerance to self-antigens, but the process is not foolproof. The thymus does not have all the self-antigens of the body available to it and rarely a T cell matures that can potentially react with various parts of the body. In these cases, other mechanisms cope with the presence of a self-reactive T cell, including clonal anergy, active suppression and sequestering.

Clonal anergy is a mechanism where T cells are made unresponsive to antigens, but are not killed. This situation is brought about by T cells reacting with antigen presented on MHC I molecules, but not receiving other signals from the immune system to multiply. Activation of T cells requires presentation of the antigen in the context of a MHC II molecule and a second receptor only found on antigen-presenting cells. Since these are self-antigens, they are not presented to the T cells by an antigen-presenting cell and are only detected on MHC I molecules. The absence of this second signal causes the T cell to shut down and become incapable of releasing IL-2 even during subsequent exposure to the antigen. Since cells expressing MHC I molecules, but not the second signal, are present throughout the body, many self-antigens are readily be encountered by a reactive T cell and it is quickly made unresponsive.

Certain T cells, called T suppressor cells, are necessary for turning down the immune system after the source of an antigen has been dealt with. Once a viral or bacterial infection is eliminated, the immune system must be suppressed to prevent further tissue damage. Remember that many of the immune reactions are themselves very damaging to tissue and it is imperative to stop these reactions as soon as they have fulfilled their purpose. T suppressor cells also have a role in protection from self-reactive antigens by mechanisms termed active suppression. It is known that normally healthy humans contain T cells that can potentially cause autoimmune disease and these cells are prevented from causing harm by the action of T suppressor cells. It has also been suggested that T suppressor cells can be induced by reaction with specific antigen, in this case a self-antigen, so that the suppression response matches any unwanted autoimmune reaction of other cells. The mechanism of how this whole process works is still not clear.

A final mechanism to deal with potential autoimmunity is the sequestering (hiding) of potentially stimulatory antigens. Some sites of the body are considered off limits to the immune system either because the immune system cannot reach the site or for some reason, immune cells cannot detect the antigen due to poor presentation. The classic example is the cornea of the eye. There are no blood vessels that run through this structure, so immune cells have no access to its antigens and therefore, no immune response can be raised. Thus, it is possible to transplant the cornea without fearing rejection by the recipient's immune system. In other cases, certain antigens are hidden away inside cells so that the immune system does not have access to them. When all of these systems fail, it can result in the manifestations of an autoimmune disease and we will discuss these later in the chapter.

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