Terminating the Immune Response

As for most things in life, turning things off in the immune system is as important as turning them on. Biologists usually like to focus on the positive, the ways in which natural processes get started. However, this is not the case for the immune system. Numerous studies have addressed the problems of resolving immune responses, perhaps because inhibition and resolution of the immune response are so important, required, as they are, to prevent autoimmunity and reduce ongoing inflammation. The body responds to infection by inducing many processes. Often granulocytes are the first cells to appear at sites of infection. Later, antigen and danger signals from the infected area arrive in draining lymph nodes, either free from cellular carriers or on migrating dendritic cells. Together these materials activate T and B cells in the nodes, causing huge expansions in the numbers of antigen-specific lymphocytes and some increases in the numbers of nonspecific cells, carried along, by various means, for the ride. These cells migrate to the site of infection, where they either directly or indirectly, by recruiting and activating other cell types, cause the destruction, elimination, or inactivation of the invading organism. After the invader has been disposed of, however, various processes that eliminate the recruited cells are brought into play. Also, there is considerable evidence that even during the acute phase of the immune response, various feedback inhibitory pathways are induced, making sure that the huge cellular expansion and cytokine storm that accompany the immune response do not overwhelm the host. With all this in mind, it is clear that immune responses are controlled and resolved in many ways. Discussions of the results of many of these studies are included in this volume. While these studies are valuable and help us to some extent understand how immunity is controlled, it is still apparent and a major problem in the field that we do not know which of the many processes dominates in different circumstances and even why the immune response is controlled in so many ways. Some of these issues are discussed in this introduction. There is another matter of historical interest associated with the results described in this volume. The scientists who proposed the elements of the clonal selection theory in the 1950s thought that the immune response would be driven entirely by antigen and that, when antigen disappeared, the immune response would cease (1-3). These scientists also expected that the primary immune response would create relatively small numbers of antigen-specific cells, cells that would survive more or less in toto, to become memory cells, when the primary infection was over. Now we know that the clonal selection theory was wrong on both these fronts. In spite of the fact that this theory accurately predicted many aspects of the immune response, it fell short in its predictions about the end of immunity, as amply demonstrated by the articles herein. For example, we now know that immune responses are accompanied by tremendous increases in the numbers of antigen-specific T cells (4-9) and to a lesser extent B cells (10). Clearly, most of these cells must be destroyed to make space, cytokines, and nutrients available for other cells and also to avoid huge amounts of inflammation were all these cells to be reactivated. Thus, biology has arranged that most of the antigen-specific cells generated during an infection disappear. The processes that control such removal are discussed at length in several articles in this volume (11-18). Nevertheless, not all antigen-induced cells die, many survive to create the memory cells (predicted by the clonal selection theorists) that protect us against reinfections (16, 19, 20).