4 D). a small subset of B cells that secrete most, if not all, natural antibodies in the apparent absence of antigenic challenge. Natural antibodies are often polyreactive and bind to foreign antigens as well as to self-components (14). B-1 cellderived natural antibodies are crucial for host survival from infections. Defects in their production cause increased deaths after contamination with bacteria, such asSalmonella typhimuriumandStreptococcus pneumoniae(57), and viruses, such as vesicular stomatitis computer virus, lymphocytic choriomeningitis computer virus, vaccinia computer virus, and influenza (2,8). B-1 cells are composed of two sister populations, CD5+B-1a and CD5B-1b (9). In addition to their disparate expression of CD5, B-1a and B-1b cells appear also to differ developmentally and functionally (10). Developmental differences between B-1a and B-1b cells were recognized by exploiting a hallmark of B-1 cells, namely their ability to self-replenish (11). B-1a and B-1b cell subsets are thought to replenish only themselves and not the other sister populace. Although the mechanisms underlying B-1 cells ability to self-replenish are not understood, earlier studies by Lalor et al. (12) revealed a homeostatic regulatory mechanism by which the presence of normal numbers of B-1 cells in the peritoneal cavity suppresses further B-1 cell growth and/or de novo development. The difference in CD5 expression between B-1a and B-1b cells might be a crucial MRS 1754 factor determining their in vivo responsiveness to pathogen invasion. CD5 functions as a negative regulator of B cell receptor (BCR)mediated activation signals (13) and renders B-1a cells nonresponsive to in vitro BCR cross-linking (14). Consistent with the expression of the inhibitor CD5 on B-1a but not B-1b cells, only CD5B-1b cells were shown to clonally expand in vivo after contamination withBorrelia hermsii. After transfer into Rag1/mice, B-1b cells rendered recipients guarded fromB. hermsiichallenge (15,16). Although B-1a cells also contributed to immune protection in that system, this was thought to be mediated via natural antibody production. Furthermore, B-1b cells created strong antiPPS-3 (pneumococcal polysaccharide-3) immune responses after immunization with either PPS-3 or heat-killedS. pneumoniaeand conferred immunity againstS. pneumoniaeafter their adoptive transfer into Rag1/recipient mice (17). B-1a MRS 1754 cells did not mount antiPPS-3 responses after immunization with heat-killedS. pneumoniae. Instead, they secreted high amounts of natural antibodies against phosphocholine, which is usually another antigenic determinant onS. pneumoniae(17). B-1b cells were also shown to mount long-term antibody responses to TI-2 (thymus-independent type-2) antigen, NP-Ficoll (4-hydroxy-3-nitrophenyl-acetyl Itgav conjugated to the polysaccharide Ficoll) (18). Collectively, these data were interpreted as evidence for a mainly passive role for CD5+B-1a cells as suppliers of natural antibodies and an active role for B-1b cells (19). However, the results from those recent studies are in apparent contrast to earlier studies that experienced demonstrated an active participation of MRS 1754 B-1a cells toS. pneumoniae(20,21). Those earlier studies exhibited that immunization led B-1a cells to generate the strong and dominant T15 idiotype antibody response to phosphocholine (20,21), which provides immune protection against reinfection withS. pneumoniae(22). Furthermore, although B-1a cells do not respond to BCR-mediated signals they strongly respond to numerous innate signals both in vivo and in vitro (13,23). Natural antibodies produced by B-1 cells are mostly of the IgM isotype (1). MRS 1754 Thus, these antibodies can also be transported MRS 1754 via the polymeric Ig receptor onto mucosal surfaces and contribute to mucosal immune defenses (24,25). We previously showed that natural IgM secretion by B-1 cells is required for maximal protection against influenza virusinduced deaths.