The memory B cells are cloned bottlenecks during the Cell-secondary immune response - old ideas for vaccine design or changes.

Adaptive immune response refers to the whole process in which antigen-specific T / B lymphocytes activate, proliferate and differentiate into effector cells and produce a series of biological effects.one of the most important characteristics of adaptive immunity is that the efficacy of immune response is significantly enhanced with repeated contact with antigen, which is more obvious in humoral immune response mediated by B cells - the number of antibodies produced by the second encounter with the same antigen is higher than that at the first encounter, and the average affinity is higher [1].this feature has been widely used in vaccination and has become the theoretical basis for the strategy of enhancing the dose to obtain and maintain the high serum antibody titer required for protection.when B cells are stimulated by antigen, they begin to undergo a series of proliferation and differentiation, forming effector B cells (also known as plasma cells, plasma cells, PC).in this process, a small number of B cells become memory B cells (MBC), which can retain the memory of antigens after months or even decades of antigen disappearance in vivo.when the same antigen enters the body again, MBC will rapidly proliferate and differentiate, forming a large number of PC, and then produce stronger specific immune response, which will clear the antigen in time.it has been found that in the process of primary immune response, some MBCs experienced somatic high frequency mutation (somatic) in germinal centers (GCS) The high affinity and the high efficiency of MBC differentiation into PC jointly produce the typical high titer of secondary immune response [2].although researchers have conducted detailed studies on the formation and reactivation of MBC at the population level, little is known about the clonal diversity of response B cells and how the clonal diversity of the final PC cell compartment is affected by the transition from primary response to secondary response.clarifying these dynamic processes will help to explain some immune phenomena, such as immune dominance and "original antigenic sin", and help us understand the rules for controlling immune responses in the context of long-standing antigenic immunity, such as influenza.at the same time, in addition to rapidly differentiating into PC, many studies believe that some MBCs can re-enter GC response after secondary immune response. However, these studies ignore the relative contribution of primary B cells to secondary germinal centers, which may compete with MBC clones, thus limiting their ability to re transform in secondary responses.it has to be said that a thorough understanding of the rules governing GC re-entry of memory B cells is important for any attempt to induce amplification and high-frequency mutation of B-cell clones with specific characteristics by repeatedly recalling MBCs into continuous GC reactions, just as it is believed that vaccination is needed to produce generalized neutralizing antibodies (bnabs) against influenza and HIV Like.recently, Professor Gabriel D. Victor from Rockefeller University in the United States published on the cell an online publication entitled "restricted clonality and limited germinal centerreentry characterize memory B cell reactivation by" This feature limits the diversity of MBC clones produced by primary response. In addition, it is found that mutated MBCs rarely re transform in secondary centers, while those entering secondary centers are mainly never entered Primordial B cells in the genetic center.in order to study the clonal kinetics of B cell secondary immune response, the researchers used typical chicken immunoglobulin (CGG) as antigen and alum adjuvant subcutaneously injected into the right hind foot pad of mice to generate primary GC in popliteal lymph nodes.30 days later, when the primary GC basically subsided, the same protein adjuvant combination was used to stimulate the contralateral foot pad of the same mouse to produce a secondary response (recall response) (Fig. 1).Figure 1 First of all, the researchers examined the clonal composition of secondary GC in this model. The results showed that the clonal diversity and SHM load of early secondary GC were similar to those of early primary GC, rather than similar to the immune memory recently generated. Therefore, the re diversification of a large number of mutated and amplified MBC clones is not the main feature of secondary GC reaction in this case 。subsequently, in order to detect the dynamic process of B cells, the researchers used aicdacreert2 / +. Rosa26confetti / confetti (aid confetti) mouse model to map the fate of activated B cells during primary response. After administration of tamoxifen, the recombinant "brainbow" multicolor fate mapping allele was induced in B cells expressing aid (encoded by aicda), and then The fate of the labeled cells was tracked after the second immunization (Fig. 2).the experimental results showed that although a small number of MBCs re entered the secondary GC, most of them were still those B cells that had never entered GC or had no clonal amplification, and the "experience" of previous entry into GC was not enough to ensure that MBC clones had a selection advantage when competing with natural B cell clones. this is the first time that it has been clearly confirmed that the secondary GC is mainly the site of de novo affinity maturation of non mutated B-cell clones, rather than the site of re diversification of mature MBCs. at the same time, this study showed that MBC derived cells could be transformed into plasmablasts (PB), but this can not be used to explain the low frequency and low diversity of MBC derived secondary generation center B cells, because the whole MBC derived secondary response is limited by Crohn. Figure 2 the comparison between the hundreds of B-cell clones obtained from primary responses and the low clonality of secondary responses derived from MBC showed that a large number of primary clonal diversity could not be effectively utilized through immune enhancement. To explore the reasons for this lack of diversity, the researchers used a second experimental system - a small initial infection with the mouse adapted influenza strain PR8 Mice were then injected subcutaneously with h1pr8 recombinant protein supplemented with adjuvant to enhance immunity. it has been found that the cloning of memory cells can be divided into two parts: one is the low clone part composed of clones in secondary GC or Pb / PC (the "used" memory cells), and the other is the highly diverse part (the "unused" memory cells) composed of clones whose secondary response is not detected The relative decrease of the ability of B cells entering the secondary GC and the clonal restriction in plasma mother cells are the common characteristics of the secondary B cell response. Although there is a clonal diversity and "unused" antigen-specific MBC population, this restriction still exists, which indicates that the enhancement of immunity focuses a broad MBC group into a narrow dominant clone group 。 however, the secondary Pb / PC produced by homologous immunopotentiation is due to repeated memory of a small number of dominant MBCs, which are usually derived from high affinity germline precursors and do not depend on the time of generation of these MBCs. this explains the secondary responses of clonal restriction and affinity maturity in MBC population with clonal diversity mainly generated in the early stage of primary response. At the same time, at the same time, it also showed that the affinity of a clone to antigen was the key factor to determine whether the clone could be effectively recalled through homologous antigen re immunization. to sum up, this study revealed two significant characteristics of clonal composition of memory B cell immune response by using the model of continuous contact with antigen in different anatomical sites: first, B cells in secondary generation center are not mainly composed of previously mature B cells, but almost completely come from new precursors without primary response experience; second, only a few memory B cells derive However, most of the diversity generated by the primary immune response turned into memory B cells with IgM + and reduced somatic high frequency mutation and could not be detected (Fig. 3). this finding means that recruitment of MBC to secondary occurrence centers through repeated immunization will be an inefficient process, which will provide new guidance for vaccine design. a better understanding of the mechanisms controlling MBC production and secondary response propensity will help us to design immune methods to allow more MBCs to re-enter secondary occurrence centers, increase the probability of continuous affinity maturation, and thus enhance the immune response response. However, overcoming the cloning bottleneck of MBC will greatly improve the ability of people to induce non immune dominant epitope antibodies through vaccination. Fig. 3 original link: Editor: xiaoxianzi reference 1. Gray, D. (1993). Immunological memory. Annu. Rev. Immune. 11, 49 – 77.2. Berek, C., Jarvis, J.M., and Milstein, C. (1987). Activation of memory and virus B cellclones in hyperimmune animals. Eur. J. Immunol. 17, 1121–1129.