How specific is too specific? B-cell responses to viral infections reveal the importance of breadth over depth

Abstract

Influenza virus infection induces robust and highly protective B-cell responses. Knowledge gained from the analysis of such protective humoral responses can provide important clues for the design of successful vaccines and vaccination approaches and also provides a window into the regulation of fundamental aspects of B-cell responses that may not be at play when responses to non-replicating agents are studied. Here, I review features of the B-cell response to viruses, with emphasis on influenza virus infection, a highly localized infection of respiratory tract epithelial cells, and a response that is directed against a virus that continuously undergoes genetic changes to its surface spike protein, a major target of neutralizing antibodies. Two aspects of the B-cell response to influenza are discussed here, namely polyreactive natural antibodies and the role and function of germinal center responses. Both these features of the B-cell response raise the question of how important antibody fine-specificity is for long-term protection from infection. As outlined, the pathogenesis of influenza virus and the nature of the antiviral B-cell response seem to emphasize repertoire diversity over affinity maturation as driving forces behind the influenza-specific B-cell immunity.

Keywords: B-1 cells; antibody repertoire; antiviral immunity; extrafollicular foci; germinal centers; plasma cells.

Fig. 1. B-1 cell redistribution following influenza infection

Published reports and our recent studies (Waffarn et al., manuscript submitted) highlight the importance of the body cavity B-1 cells as reservoirs of innate-like lymphocytes. B-1 cells appear to continuously recirculate in and out of the body cavities. After influenza virus infection, pleural cavity B-1 cells receive infection-induced signals that alter their gene expression. Type I IFN direct signaling enables B-1 cells to respond to the infection with increased accumulation in the inflamed lymph nodes at the site of infection. This accumulation may reduce the number of B-1 cells that can circulate back into the body cavities.

Fig. 2. Timeline of B-cell responses during influenza infection

Within 24-48 h following influenza infection B-1a cells will accumulate in the regional lymph nodes and secrete both virus-specific and virus non-specific natural IgM. By days 3 or 4, the first IgM, IgG or IgA-producing plasmablasts are measurable. They are generated in extrafollicular foci and are mainly, albeit not exclusively, T-dependent. Germinal centers do not develop until about day 7. By that time most of the infectious virus has been cleared from the respiratory tract. Germinal centers can be found up to 5 months after influenza infection. Germinal center responses generate both long-lived plasma cells in the bone marrow as well as circulating memory B cells. Plasma cells and memory B cells are also found in the lung, were they persist for many months and even years. Their origins have not been resolved.

Fig. 3. Germinal center persistence after influenza infection

Shown are the mean frequencies ± SD (n = 4-6 mice/group) of germinal center B cells among all CD19+ B cells in the regional lymph nodes at indicated times following influenza A/Puerto Rico/8/34 infection of BALB/c mice. Note the long persistence of the germinal centers, despite viral clearance around day 7. The data were as reported previously (86).

Fig. 4. B-cell responses to influenza infection differ in the diversity of their BCR repertoire

There are at least three distinct B-cell response types that contribute to immune protection from influenza infection: B-1 cells respond to infection with the secretion of polyreactive, natural IgM, some but not all of which binds to influenza virus. These antibodies are overall of low affinity, but they can bind to many different types of antigens and their presence is required from survival from infection. Second, germinal center-derived B-2 cell responses become polyclonal over time, facilitated in part through somatic hypermutation in the antigen-binding CDR3-Ig region. While these responses generate high-affinity antibodies against the infection at hand, continued germinal center reaction can also result in the generation of polyreactive antibodies. Moreover, the repertoire of B cell clones that participate in the immune response is expanded over time. Finally, the extrafollicular foci response, which can be of high affinity, but is likely highly oligoclonal during a primary infection, as it relies on the presence of high-affinity germline-encoded antigen-specific B cells. However, these responses are supplemented by memory B cells, which can participate in a recall response by rapidly forming extrafollicular foci.