The Role of Biological Sex in the Self-renewal of B1 Cells into Old Age in Mice and Humans

Project Summary/Abstract By the year 2050 the WHO predicts there will be 2 billion people aged 60 years and over. As the population of aged individuals rises so will aging-associated diseases. To create better prevention strategies for diseases in the elderly, we need to address fundamental biological questions regarding immune system deterioration during the aging process. Specifically, the goal of this proposal is to determine whether defects in natural immunity in the aged are due to changes in self-renewal of a subset of B cells, B1 cells, which produce natural antibodies (NAbs). NAbs are generated in the absence B1 cell stimulation and constitute a key modality of serological immunity providing many essential functions within in immune system. The effectiveness of NAbs is attributed to their distinct germline-like properties that result from development of B1 cells during fetal life with persistence into adulthood. Our studies demonstrate NAbs are less effective at providing protection in aged males yet, protection is maintained in aged females. If effective NAbs are maintained over a lifetime, these essential proteins could aid in producing an increase in both health-span and lifespan; yet it is unknown how protective NAbs are maintained in aged females but not aged males. This loss in NAb protection against infection in aged males is not accounted for by a change in the amount of antigen specific antibody, but instead, is due to the loss of antibody germline-like features, which does not occur in aged females, where B1 cell derived antibody remains germline-like. Our preliminary and published results suggest these findings are a result of better persistence of B1 cells that originate in fetal life with advancing age in females as opposed to males. The reason for this is unknown but it is speculated that B1 cell self-renewal is responsible. We hypothesize age and sex-associated defects in the protective capacity of natural IgM results from loss of adult B1 cell self-renewal in aged males but not aged females. To test this hypothesis, we will utilize advanced genetic techniques that provide the means for the first time to separately track B1 cells originating in fetal life from those arising in adult life, and for the first time to measure the stage at which B1 cells are in cell cycle, according to sex and age. We will 1) determine how biological sex influences long term persistence of mouse B1 cells generated during different phases of life; 2) examine sex specific regulation of mouse B1 cell cycle progression and self-renewal with increasing age; and 3) evaluate the role of sex in specifying human B1 cell cycle dynamics and human B1 cell natural antibody function. This project will elucidate mechanisms of differential B1 cell self-renewal in aged males and females, which will provide critical information for designing novel approaches to maintain healthy natural immunity into old age by favoring self - renewal of early appearing B1 cells.