Intermittent fasting alters the antigen-specific CD5+ B-1 cell natural antibody repertoire in male and female mice.

Natural antibodies (NAbs), primarily produced by CD5+ B-1 cells, provide critical early protection against infections such as Streptococcus pneumoniae. The structure of these natural antibodies, germline-like with minimal N-additions, is essential for their protective capacity. The protective capacity and germline status of NAbs are compromised in aged male mice but maintained in aged female mice. CD5+ B-1 cells are maintained through self-renewal, necessary for maintaining germline-like natural antibodies, and this process depends on autophagy. Intermittent fasting enhances autophagy and stem cell self-renewal, suggesting that it may influence B-1 cell persistence and natural antibody structure. Young (4-wk-old) male and female mice were placed on a fasting regimen (24-h fast weekly) or fed ad libitum for 12 wk. Here, we show that intermittent fasting modulates the antigen-specific natural IgM repertoire of young male and female mice, altering both peritoneal and splenic phosphatidylcholine-specific CD5+ B-1 cell repertoires, with the most pronounced effects in the spleen. Intermittent fasting increased the prevalence of germline-like (few N-additions) antibodies and led to an increase in VH11 usage, a variable gene mainly utilized during fetal development. Fasting also affected components of the serum repertoire; however, these effects differed between male and female mice. Female mice showed a significant decrease in phosphorylcholine- and pneumococcal polysaccharide serotype 3-specific IgM levels, whereas male mice showed a significant increase in phosphatidylcholine-specific IgM levels. We also observed a significant decrease in splenic CD5+ B-1 cells and serum interleukin-5 levels after fasting. These results suggest that intermittent fasting may help preserve or restore protective NAbs.