Date of Award

1-1-2013

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biomedical Sciences

Content Description

1 online resource (xvi, 137 pages) : illustrations (some color)

Dissertation/Thesis Chair

Gary M Winslow

Committee Members

William Lee, Jeff Kennedy, Paul Masters, Elizabeth Leadbetter

Keywords

B cells, humoral, IgM, immunological memory, Immunologic memory, Immunoglobulin M, Immunity

Subject Categories

Immunology of Infectious Disease

Abstract

Immunological memory is a fundamental concept that is key to generating and maintaining immunity to pathogens. Humoral memory resides in part in antigen-specific memory B cells, which are classically defined as class-switched, somatically mutated, long-lived cells that are highly responsive to specific antigen challenge. Despite the focus on class-switched memory B cells, several studies have validated the existence of IgM memory B cells, and have demonstrated distinct functions of IgM and IgG memory B cell subsets. Based on the expression of CD11c, we have identified a large population of IgM memory B cells using a natural model of infection by the bacterium Ehrlichia muris. This long-term CD11c+ IgM B cell population exhibited phenotypic characteristics of memory B cells, including expression of CD73, and PD-L2. In addition, the CD11c+ IgM memory B cells lacked expression of CD138, were largely quiescent, and accumulated somatic mutations. Although these cells did not proliferate or secrete antibody ex vivo, they produced antigen-specific IgM upon in vitro stimulation with mitogens. The CD11c+ IgM memory B cells were located in the splenic marginal zone, but were not detected in blood or other secondary lymphoid organs. In vivo depletion of the CD11c-positive IgM memory B cells caused a transient decrease in long-term IgM production, and abrogated the IgG recall response to specific antigen challenge. These results indicate that the IgM memory B cells were responsible for both the maintenance of serum Ig, and humoral memory. Generation of the IgM memory B cells was independent of the infectious doses tested, and required CD4 T cells, Bcl-6, and IL-21R signals. In vivo labeling of AID-expressing cells revealed that the IgM memory B cells were generated during acute infection, and as early as day 4 post-infection. Our findings demonstrate that T cell-dependent IgM memory B cells can play an important role in maintaining long-term immunity during bacterial infection.

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