Antigen-specific memory in B-1a and its relationship to natural immunity

Abstract

In the companion article by Yang and colleagues [Yang Y, et al. (2012) Proc Natl Acad Sci USA , 109, 10.1073/pnas.1121631109], we have shown that priming with glycolipid (FtL) from Francisella tularensis live-vaccine strain ( i ) induces FtL-specific B-1a to produce robust primary responses (IgM >>IgG); ( ii ) establishes persistent long-term production of serum IgM and IgG anti-FtL at natural antibody levels; and ( iii ) elicits FtL-specific B-1a memory cells that arise in spleen but rapidly migrate to the peritoneal cavity, where they persist indefinitely but divide only rarely. Here, we show that FtL rechallenge alone induces these PerC B-1a memory cells to divide extensively and to express a unique activation signature. However, FtL rechallenge in the context of a Toll-like receptor 4 agonist-stimulated inflammatory response readily induces these memory cells to migrate to spleen and initiate production of dominant IgM anti-FtL secondary responses. Thus, studies here reveal unique mechanisms that govern B-1a memory development and expression, and introduce B-1a memory as an active participant in immune defenses. In addition, at a practical level, these studies suggest previously unexplored vaccination strategies for pathogen-associated antigens that target the B-1a repertoire.

H–Y antigen-binding B cells develop in male recipients of female hematopoietic cells and associate with chronic graft vs. host disease

“…As is usual in studies with antigen-binding B cells in the mouse (21,22), the amount of the antigen bound to the B cells is strongly correlated with the amount of surface Ig on the cells, which at the time point we examined is exclusively IgM and IgD associated mainly with Igλ light chains. However, even though these cells have most likely arisen in response to antigenic stimulation (DBY-2 on the male patient's cells stimulating female donor B cells), they express a phenotype (CD19 + IgM + IgD + CD38 + and CD27ˉ) commonly taken as characteristic of transitional B cells that have recently entered circulation from bone marrow.…”

Expression of plasma cell alloantigen 1 defines layered development of B-1a B-cell subsets with distinct innate-like functions

“…It may be that the small numbers of PC1 hi cells that migrate to the spleen are the precursors to splenic IgM-secreting cells, similar to the migratory cells found to respond to stimulation with the atypical LPS of F. tularensis (52).…”

Antigen-specific antibody responses in B-1a and their relationship to natural immunity

“…4), in which the same materials and methods are used. All of the animal experiment protocols are approved by Stanford Animal Care Review Board.…”

“…However, in this and a companion article (see ref. 4), we demonstrate that immunization with a glycolipid (FtL) isolated from Francisella tularensis live-vaccine strain (Ft LVS) readily induces splenic FtL-specific B-1a to produce T-independent antigenspecific IgM and IgG (IgM>>IgG) primary antibody responses, to develop long-term antigen-specific memory, and to produce secondary antibody responses when appropriately rechallenged with the antigen. Strikingly, although the B-1a memory responses that we identify share many of the properties of B-2 memory responses, they nonetheless differ in key ways that make the B-1a responses more suitable for the functional niche they occupy.…”