B1B lymphocytes generate T cell-independent memory

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DESCRIPTION (provided by applicant): Overwhelming bacteremia is one of the leading causes of death by infectious disease in the United States. A critical factor in preventing bacteremia from evolving into a life-threatening infection is the ability of the host to rapidly generate protective antibodies against the invading pathogens. T cell-independent (Tl) responses are highly protective and develop significantly more rapidly than T cell-dependent (TD) responses. However, Tl responses have been long considered exclusively short-lived and incapable of conferring long-lasting protection. The relapsing fever bacterium Borrelia hermsii grows to exceedingly high concentrations in the blood, but is rapidly cleared in a Tl manner. We have utilized a murine model of B. hermsii infection to show that this Tl response in fact generates long-term protection. This immunity is conferred by B1b lymphocytes, a novel subset of B cells whose functions are not yet well understood. These B1b cells expand concurrent with the resolution of B. hermsii infection, persist, and secrete protective IgM. Interestingly, while B1b cells from convalescent mice confer complete protection when transferred to immunodeficient mice, naive B1b cells provide only partial and short-lived immunity, indicating that the convalescent B1b cells have apparently acquired immunological memory. To understand the basis of this Tl memory-like response, and to identify the specific antigen(s) targeted by B1b cells, the following questions will be addressed: (1) What B. hermsii antigens are recognized by protective B1b-derived IgM? IgM monoclonal antibodies (mAbs) will be generated from hybridomas derived from convalescent B1b cells and the B. hermsii antigens recognized by those IgM mAbs will be identified and mAbs will also be tested for the ability to kill this bacterium in vitro and protect mice in vivo. (2) What is the frequency and protective capability of B. hermsii-specific B1b cells of naive and convalescent mice? Frequencies will be determined by flow cytometry and ELISPOT and VH CDR3 spectratyping. (3) What are the intrinsic differences between antigen-specific B1b cells of convalescent and naive mice? Kinetics of cell proliferation to a variety of stimuli and differentiation into antibody-secreting cells in response to B. hermsii will be assessed in vitro and in vivo. Understanding the basis for the longevity of the Tl protective responses conferred by B1b cells will provide novel approaches to generate effective vaccines against pathogens expressing Tl antigens.