These findings show that immunological memory need not be maintained by repeated exposure to infectious virus. Instead, it is likely that memory is sustained by long-lived antigen-specific lymphocytes that were induced by the original exposure and that persist until a second encounter with the pathogen. Although most of the memory cells are in a resting state, a small percentage of memory cells are dividing at any one time. It appears that this turnover is maintained by cytokines, such as IL-7 and IL-15, produced either constitutively or during antigen-specific immune responses directed at other, non-cross-reactive antigens. The number of memory cells for a given antigen is highly regulated, persisting with a relatively long half-life balanced by cell proliferation and cell death.
Immunological memory can be measured experimentally in various ways. Adoptive transfer assays (see Appendix I, Section A-30) of lymphocytes from animals immunized with simple, nonliving antigens have been favored for such studies, because the antigen cannot proliferate. In these experiments, the existence of memory cells is measured purely in terms of the transfer of specific responsiveness from an immunized, or ‘primed,’ animal to a nonimmunized recipient, as tested by a subsequent immunization with the antigen. Animals that received memory cells have a faster and more robust response to antigen challenge than do controls that did not receive cells, or that received cells from nonimmune donors.
Experiments like these have shown that when an animal is first immunized with a protein antigen, functional helper T-cell memory against that antigen appears abruptly and reaches a maximum after 5 days or so. Functional antigen-specific B-cell memory appears some days later, then enters a phase of cell proliferation and selection in lymphoid tissues. By 1 month after immunization, memory B cells are present at their maximum level. These levels of memory cells are then maintained, with little alteration, for the lifetime of the animal. It is important to recognize that the functional memory elicited in these experiments can be due to the precursors of memory cells as well as the memory cells themselves. These precursors are probably activated T cells and B cells, some of whose progeny will later differentiate into memory cells. Thus, precursors to memory cells can appear very shortly after immunization, even though resting memory-type lymphocytes may not yet have developed.
In the following sections we look in more detail at the changes that occur in lymphocytes after antigen priming and lead to the development of resting memory lymphocytes, and discuss the mechanisms that might account for these changes.
11-18 Memory B-cell responses are more rapid and have higher affinity for antigen compared with responses of naive B cells.
Immunological memory in B cells can be examined in vitro by isolating B cells from immunized or unimmunized mice and restimulating them with antigen in the presence of helper T cells specific for the same antigen (Fig. 11.24). B cells from immunized mice produce responses that differ both quantitatively and qualitatively compared with naive B cells from unimmunized mice. B cells that respond to the antigen increase in frequency by up to 100-fold after their initial priming in the primary immune response. Further, due to the process of affinity maturation (described in Chapter 10), antibodies produced by B cells of immunized mice typically have higher affinity for antigen than antibodies produced by unprimed B lymphocytes. The response from immunized mice is due to memory B cells that arise in the primary response. Memory B cells can arise from the germinal center reaction during a primary response, and may have undergone isotype switching and somatic mutations there. But memory B cells can also arise independently of the germinal center reaction from short-lived plasma cells produced in the primary response. In either case, they circulate through the blood and take up residence in the spleen and lymph nodes. Memory B cells express some markers that distinguish them from naive B cells and plasma cells. One marker of memory B cells is simply