Functional studies on natural IgM secreting B-1 cells and their roles in innate anti-viral IgM immunity against influenza virus infection

A small subset of B lymphocytes, termed B-1 cells, continuously secrete polyspecific "natural antibodies" in steady-state in the absence of pathogenic stimulation in humans and mice, thereby contributing to immune protection against many pathogens, including influenza virus. Given the unusual characteristics of this B lymphocyte subset that displays both innate and adaptive immune characteristics, the main aim of this dissertation work was to identify mechanisms of B-1 cell regulation in steady-state and during influenza virus infection.;Work outlined in Chapter 2 elucidated the tissue locations and the regulation of steady-state natural IgM production. The studies identify a novel B-1 cell population in the bone marrow of mice that, together with splenic B-1 cells is responsible for much of the natural IgM production. The study further indicates that novel differentiation pathways must regulate the bone marrow B-1 cells as they expressed a transcriptional expression profile that was not inducible in peripheral B-1 cells by either antigen-specific or mitogenic activation signals.;Chapter 3 reveals the highly localized nature of the B-1 cell response to influenza virus infection. B-1 cells were shown to accumulate in the mediastinal lymph nodes (MedLN) following influenza infection by mechanisms distinct from those of conventional B cells. B-1 cell responses lacked any signs of antigen-specificity, such as participation in germinal centers or clonal expansion. Instead, infection-induced innate immune signals seemed to cause the accumulation of polyspecific B-1 cells, enabling them to contribute to both virus-specific as well as non-specific IgM to the respiratory tract.;Studies described in Chapter 4 confirm the redistribution of B-1 cells from the pleural cavity and possibly the bone marrow to the MedLN after influenza virus infection. Studies in IL-1R1-/- mice identify the influenza infection-induced elaboration of the proinflammatory cytokine IL-1 as a potential mechanism regulating the mobilization of bone marrow B-1 cells into the MedLN and their subsequent differentiation to antibody-secreting cells. Collectively these studies provides novel information on the regulation of the polyspecific B-1 cell response, thereby identifying these cells as potential targets for prophylactic and therapeutic treatments that can elicit "useful" poly-specific responses to known and unknown pathogens.