During a secondary exposure to infection, antibodies persisting from a primary immune response are available immediately to bind the pathogen and mark it for degradation by complement or by phagocytes. If the antibody can completely neutralize the pathogen, a secondary immune response may not occur. Otherwise, excess antigens will bind to receptors on B cells and initiate a secondary response in the peripheral lymphoid organs. Memory B cells recirculate through the same secondary lymphoid compartments as naive B cells, principally the follicles of the spleen, lymph nodes, and the Peyer’s patches of the gut mucosa. B cells with the highest avidity for antigen are activated first. Thus memory B cells, which have been selected previously for their avidity to antigen, make up a substantial component of the secondary response.
Besides responding more rapidly, memory B cells can reenter germinal centers during secondary immune responses and undergo additional somatic hypermutation and affinity maturation, as described in Sections 10-6 through 10-8. As in primary responses, secondary B-cell responses begin at the interface between the T-cell and B-cell zones, where memory B cells that have acquired antigen can present peptide:MHC class II complexes to helper T cells. This interaction initiates proliferation of both the B cells and T cells.
Reactivated memory B cells that have not yet undergone differentiation into plasma cells migrate into the follicle and become germinal center B cells, undergoing additional rounds of proliferation and somatic hypermutation before differentiating into antibody-secreting plasma cells. Since B cells with the higher-affinity antigen receptors will more efficiently acquire and present antigen to antigen-specific TFH cells in the germinal center, the affinity of the antibodies produced during secondary and tertiary responses rises progressively (see Fig. 10.14).
increased frequency relative to their frequency as naive
T cells.
Until relatively recently, analysis of T-cell memory relied on assays of T-cell function rather than a direct identification of antigen-specific memory T cells. Some assays of T-cell effector function, such as providing help to B cells or macrophages, can take several days to perform. Because of this, such assays are not optimal for distinguishing memory T cells from preexisting effector cells, since memory cells can be reactivated during the time frame of the assay. This is a problem particularly for effector CD4 T cells, but does not apply as much for effector CD8 T cells, which can program a target cell for lysis in 5 minutes. In contrast, memory CD8 T cells need more time than this to be reactivated to become cytotoxic, so that the actions of memory CD8 T cells will appear much later than those of preexisting effector cells.
Examining T-cell memory has been made easier by the development of MHC tetramers (see Appendix I, Section A-24). Before MHC tetramers, effector and memory responses were studied using naive T cells from mice carrying specific T-cell receptor (TCR) transgenes. Such TCR-transgenic T cells could be uniquely identified by antibodies to their rearranged T-cell receptors, but were not part of the host’s natural T-cell repertoire. MHC tetramers measure the in vivo frequency of all clones with a given antigen specificity, but do not distinguish between different T-cell clones of the same specificity. MHC tetramers were generated for MHC class I molecules first, but are now also available for some MHC class II molecules, allowing the study of both CD8 and CD4 T cells both in normal mice and in humans.
MHC tetramers have allowed a direct analysis of the formation of memory T cells. In the example shown in Fig. 11.26, T-cell responses to infection by the intracellular bacteria Listeria monocytogenes are analyzed with MHC class II tetramers specific to the toxin listeriolysin O (LLO). In the naive T-cell repertoire of the mouse, there are approximately 100 LLO-specific CD4 T cells, which undergo 1000-fold expansion into effector T cells during the