A similar suppression of naive T-cell responses by antigen-specific memory T cells can occur in the setting of infection by lymphocytic choriomeningitis 1000 100 10 A B C D E F G Response to epitope Response to epitope Response to epitope A B C D E F A B C D Percentagenormal response 1000 100 10 Percentagenormal response 1000 100 10 Percentagenormal response Same individual at 20 years infected with a new variant in˜uenza virus makes antibody only against epitopes shared with original virus, not against epitopes shared with the variant encountered at age 5 years Same individual at 5 years infected with a variant in˜uenza virus makes antibody only against the epitopes shared with the original virus Individual at 2 years infected with in˜uenza virus makes antibody against all epitopes present on the virus
Fig. 11.34 When individuals who have been infected with one influenza virus responds preferentially to those epitopes shared variant of influenza virus are infected with a second or third with the original virus, and makes a smaller than normal response variant, they make antibodies only against epitopes that were to new epitopes on the virus (center panel). Even at age 20 years, present on the initial virus. A child infected for the first time with this commitment to respond to epitopes shared with the original an influenza virus at 2 years of age makes a response to all epitopes virus, and the subnormal response to new epitopes, is retained (right (left panel). At age 5 years, the same child exposed to a different panel). This phenomenon is called ‘original antigenic sin.’ virus (LCMV) in the mouse or dengue virus in humans. Mice that were primed with one strain of LCMV responded to a subsequent infection with a second strain of LCMV by expanding CD8 T cells that reacted to antigens specific for the first strain. However, this type of effect was not observed when responses to variable ovalbumin antigenic epitopes were examined in the setting of recurrent infections using the bacterial pathogen Listeria monocytogenes, suggesting that the suppression caused by ‘original antigenic sin’ does not occur in all immune responses.
Summary.
Protective immunity against reinfection is one of the most important consequences of adaptive immunity, and results from the establishment of populations of long-lived memory B cells and memory T cells. These antigen-specific memory cells arise from the populations of lymphocytes that expand dramatically during the primary infection, and that survive at higher frequencies than in the naive lymphocyte repertoires. Both their increased frequency and their capacity to respond more rapidly to restimulation to the same antigen contribute to protective immunity, which can be transferred to naive recipients by memory B and T cells. Memory lymphocytes are maintained by their expression of receptors for cytokines, such as IL-7 and IL-15, that provide survival signals. Memory B cells can be distinguished by changes in their immunoglobulin genes because of isotype switching and somatic hypermutation, and secondary and subsequent immune responses are characterized by antibodies with increasing affinity for the antigen. The advent of receptor-specific reagents—MHC tetramers—has allowed for the direct analysis of the expansion and differentiation of effector and memory T cells. We now recognize that T-cell memory is complex, and memory T cells are quite heterogeneous, having central memory, effector memory, and tissue-resident memory subtypes. While CD8 T cells can generate effective primary responses in the absence of help from CD4 T cells, it is becoming clear that CD4 T cells have an integral role in regulating CD8 T-cell memory. These issues will be critical in understanding, for example, how to design effective vaccines for diseases such as HIV/AIDS.
Summary to Chapter 11.