Sex Specific Regulation of B1 B Cell Self-Renewal and Natural Antibody Production

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PROJECT SUMMARY/ABSTRACT Lower respiratory tract infections such as pneumonia claims the lives of approximately 4 million people worldwide each year, making these infections fourth on the list of global causes of death. Streptococcus pneumoniae is the most common cause of pneumonia leading to death in individuals over the age of 65 eight times more frequently than those aged 5-49, despite the long-standing availability of a vaccine for this age group (approved in 1983). In both murine and human systems, there is a greater incidence of, and susceptibility to, pneumococcal infection in males; nevertheless, the factors contributing to this difference between males and females are unknown. Therefore, the long-term goal of this study is to gain a greater understanding of the immune system in the context of sex. Specifically, the goal of this proposal is to determine whether sex and/or anatomical location influences a specific subset of B cells, B1 cells, which provide essential protection and therefore survival from S. pneumoniae infection through production of natural antibodies. Antibodies provide defense against infection by binding the pathogen and preventing infection of host cells. Natural antibodies are present in the absence of infection or intentional immunization. B1 cells’ unique ability to provide protection against S. pneumoniae is attributed to their production of natural antibodies, which have unique structural characteristics resulting from their fetal development. Fetal derived B1 cells maintain their population through a self-renewal process, which is unlike the B cell subset, B2 cells, generated from hematopoietic stem cells. Therefore, self-renewal is essential for the maintenance of natural antibodies protective against infection, though little is known about how sex influences self-renewal of B1 cells into old age. We have demonstrated natural antibody from aged male mice does not provide protection against S. pneumoniae infection whereas, natural antibody from aged females maintains its protective capacity. We hypothesize that maintenance of B1 cells through self-renewal is influenced by sex during aging. We postulate that female B1 cells maintain more productive B1 self-renewal allowing for the differences seen in susceptibility to infection with sex and age. To test this hypothesis, we will perform the following aims: 1) elucidate the sex-specific developmental differences regulating B1 cells by examining cell cycle maintenance through a unique transgenic reporter line combined with examination of self-renewal to determine the functional consequence of sex, age, and cell cycle activity on the production of protective antibody and 2) determine how maintenance of self-renewal in humans may mirror the murine system and influence production of natural antibody. This project will determine how sex influences the maintenance of B1 cell self-renewal and the subsequent impact on the production of natural antibodies during aging. This further understanding of the immune system in context to sex will likely suggest new prevention and/or treatment strategies of S. pneumoniae infection in both male and female aging populations.