Infectious diseases are the leading cause of death worldwide and vaccination is the most effective means to control them. Persistence of memory B cells generated by vaccination is critical for the longevity of protective immunity, but the molecular mechanism required for their long-term maintenance is unknown. B cell responses generated in the absence of T cell-help to bacterial polysaccharides are short-lived and such responses are inefficient in generating B cell memory. Using the experimental model of Borrelia hermsii bacteremia, we discovered a novel role for B1b cells, a subset of mature B cells, in long-lasting memory responses in the absence of T cell-help. Specifically, we found that B1b cells expand concurrently with the resolution of B. hermsii bacteremia and persist for long time periods. B1b cells from convalescent mice but not from naive mice generate a specific antibody response and confer long-lasting immunity, indicating that the protective response corresponds to B1b cell persistence as in the case of conventional B cell memory. B cell responses to T cell- independent antigens such as bacterial polysaccharides are generated primarily by cross-linking B cell antigen receptors (BCR). Although B1b cells recognize a variety of bacterial polysaccharides, such antigens do not induce antibody responses in X-linked immunodeficient mice (xid) mice, which have a mutation in the gene encoding for Bruton's tyrosine kinase (Btk), which is required for optimal BCR-mediated signaling. In contrast, B. hermsii induces not only a specific antibody response but also a selective expansion of B1b cells in xid mice. These expanded B1b cells persist for long time periods, conferring upon the convalescent xid mice resistance to re-infection. These data suggest that immunostimulatory mechanisms other than BCR signaling can play an important role in the generation and maintenance of T cell-independent B1b cell memory. We found that B. hermsii is capable of activating Toll-like receptors (TLRs) and mice deficient in both Btk and MyD88, an adaptor protein required by multiple members of the TLR family, are severely impaired in mounting protective responses indicating that a coordinated signaling through BCR and TLRs is critical. We have also found that TLR and BCR signaling pathways synergize to upregulate BAFFR, one of the major receptors for B cell activating factor of the tumor necrosis factor family (BAFF, also known as BLyS), on B1b cells in vitro. Furthermore, we found that immunization with whole bacteria also induces BAFFR up-regulation on expanded antigen-specific B1b cells in vivo. BAFF, by engaging BAFFR, induces the expression of the pro-survival molecules Mcl-1 and Bcl-XL and kinases involved in cellular metabolic fitness and B cell homeostasis. These findings led us to hypothesize that B1b cells that have responded to both BCR and TLR stimulation exhibit an enhanced BAFFR signaling and are preferentially maintained over naive B1b cells or B1b cells that are stimulated by BCR alone. Identification the role of TLR and BAFF signaling in B1b cell long-term maintenance will provide novel approaches for the generation of effective polysaccharide vaccines.
Infectious diseases are the leading cause of mortality and morbidity worldwide, and vaccination is the most effective means to control them. Polysaccharide vaccines do not generate long-lasting immunity and current strategies have a number of limitations. Understanding the role of Toll-like receptor signaling in the long-lasting protective memory responses conferred by B1b cells will provide novel approaches to generate effective vaccines.
| Dickinson, Gregory S; Akkoyunlu, Mustafa; Bram, Richard J et al. (2015) BAFF receptor and TACI in B-1b cell maintenance and antibacterial responses. Ann N Y Acad Sci 1362:57-67 |
