Antigen Receptor Specificity and Cell Location Influence the Diversification and Selection of the B-1a Cell Pool with Age.

Abstract

B-1a cells provide immediate and essential protection from infection through production of natural Ig, which is germline-like due to minimal insertion of N region additions. We have previously demonstrated peritoneal B-1a cell-derived phosphorylcholine-specific and total IgM moves away from germline (as evidenced by an increase in N-additions) with age as a result of selection. In young mice, anti-phosphatidylcholine Abs, like anti-phosphorylcholine Abs, contain few N-additions, and have been shown to be essential in protection from bacterial sepsis. In this study, we demonstrate the germline-like status of phosphatidylcholine (PtC)-specific (PtC+) peritoneal B-1a cell IgM does not change with age. In direct contrast, the splenic PtC+ B-1a cell population does not preserve its IgM germline status in the aged mice. Furthermore, splenic PtC+ B-1a cells displayed more diverse variable gene segments of the H chain (VH) use in both the young and aged mice as compared with peritoneal PtC+ B-1a cells. Whereas the peritoneal PtC+ population increased VH12 use with age, we observed differential use of VH11, VH12, and VH2 between the peritoneal and splenic PtC+ populations with age. These results suggest disparate selection pressures occur with age upon B-1a cells expressing different specificities in distinct locations. Overall, these results illuminate the need to further elucidate how B-1a cells are influenced over time in terms of production and selection, both of which contribute to the actual and available natural IgM repertoire with increasing age. Such studies would aid in the development of more effective vaccination and therapeutic strategies in the aged population.