One important reason is that the adaptive immune system “learns” not to respond to self molecules. Normal mice, for example, cannot mount an immune response against one of their own protein components of the complement system called C5 (see Figure 24–7). However, mutant mice that lack the gene encoding C5 but are otherwise genetically identical to normal mice of the same strain can make a strong immune response to this blood protein when immunized with it. The immunological self-tolerance exhibited by normal mice persists only for as long as the self molecule remains in the body: if a self molecule such as C5 is experimentally removed from an adult mouse, the animal gains the ability to respond to it after a few weeks or months, as new B and T cells develop in the absence of C5. Thus, the adaptive immune system is genetically capable of responding to self molecules, but it learns not to do so.
Self-tolerance depends on a number of distinct mechanisms, including the following (Figure 24–21): 1.
In receptor editing, developing B cells that recognize self molecules change their antigen receptors so that the cells no longer do so.
2.
In clonal deletion, potentially self-reactive B and T cells die by apoptosis when they encounter their particular self molecule.
Figure 24–20 A simplified drawing of a human lymph node. B cells are primarily clustered in structures called lymphoid follicles, whereas T cells are found mainly in the paracortex. chemokines attract both types of lymphocytes into the lymph node from the blood via postcapillary venules (see Figure 24–19). B and T cells then migrate to their respective areas, attracted by different chemokines. If they do not encounter their specific antigen, both B cells and T cells then enter the medullary sinuses and leave the node via the efferent lymphatic vessel. This vessel ultimately empties into the bloodstream, allowing the lymphocytes to begin another cycle of circulation through a peripheral lymphoid organ (see Figure 24–18). During an infection, proliferation of pathogen-specific B cells produces a germinal center in some lymphoid follicles.
3.
In clonal inactivation (also called clonal anergy), self-reactive B and T cells become functionally inactivated when they encounter their self molecule.
4.
In clonal suppression, self-reactive regulatory T cells (discussed later) suppress the activity of other types of potentially self-reactive lymphocytes.
Some of these mechanisms—especially the first two, receptor editing in B cells and clonal deletion of B and T cells—operate in central lymphoid organs when newly formed self-reactive B and T cells first encounter their self molecules, and they are largely responsible for the process called central tolerance. Clonal inactivation and clonal suppression, by contrast, operate mainly when mature B and T cells encounter their self molecules in peripheral lymphoid organs, and they are largely responsible for the process called peripheral tolerance. Clonal deletion, however, can also operate peripherally, and clonal inactivation can also operate centrally.
Why does the binding of a self molecule lead to tolerance rather than activation? The answer is still not completely known. As we discuss later, the activation of a B or T cell by its antigen in a peripheral lymphoid organ requires more than just antigen binding: it requires co-stimulatory signals, which are provided by a helper T cell (discussed later) in the case of a B cell and by an activated dendritic cell in the case of a naïve T cell. The production of such signals is usually triggered by exposure to a pathogen, but a self-reactive lymphocyte normally encounters its self antigen in the absence of such signals. Under these conditions, the lymphocyte will not only fail to be activated, it will often be rendered tolerant—being either killed or inactivated, or actively suppressed by a regulatory T cell (see Figure 24–21). In peripheral lymphoid organs, both T cell tolerance and activation usually occur on the surface of a dendritic cell.