Coughlan, Ruth Elizabeth (2012)
Ph.D. thesis, University of Birmingham.
Immunity to Salmonella infection requires an integrated immune response, encompassing Th1 cell-mediated and humoral immunity at discrete stages of infection. Primary infection of mice with attenuated Salmonella Typhimurium (STm) drives an atypical B cell response, characterised by a rapid expansion of extrafollicular (EF) plasma cells which precedes germinal centre (GC) formation. This thesis examines elements of the GC and EF antibody response, and their regulation.
We show that the signalling, adhesion receptor CD31, the cytokines IL4, IL13 and IL6, and the transcription factor T-bet, have selective roles in regulating facets of the B cell response to STm. Antibody responses are severely impaired in CD31-/- mice during primary infection, as is protective immunity after subunit immunisation. The Th2-associated cytokines IL4, IL13 and IL6 promote optimal GC formation during STm infection, however only total loss of IL6 leads to defective class-switched antibody production. We further identify a B cell-intrinsic role for T-bet in IgG2a class-switching during STm infection, whilst T cell-intrinsic T-bet is completely dispensable for this response. In addition, a selective role for T-bet in GC responses to Th2 antigens is shown. These data identify some similarities and differences between the regulation of B cell responses to Th1 and Th2 antigens.
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