Date of Award

2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Steven L. Reiner

Second Advisor

E J. Wherry

Abstract

Antibody responses are one of the major defense mechanisms that mammals employ against microbial infections. As such, these responses have been targeted by most vaccine regimens used to prevent infections. However, in spite of the success of current vaccines, our understanding of how humoral immune responses develop is incomplete. A better understanding of the immunology behind humoral immunity will help in the future design of effective vaccine regimens. Much of the work done toward understanding humoral immunity has focused on the germinal center (GC) reaction. GC reactions are initiated after infections and vaccinations when B cells are activated through the B cell receptor (BCR) and interact with the other members of the responding immune system, including helper T cells. GC B cells proliferate while improving their BCR, and ultimately go on to differentiate into plasma cells that secrete protective antibodies and memory B cells that can respond to re-infection in the future. The extrinsic mechanisms by which GC B cells adopt these mutually exclusive fates have been extensively researched, but we considered that GC B cells may exercise cell-intrinsic control over their differentiation. Specifically, we hypothesized that GC B cells use asymmetric cell division to accomplish the multiple tasks set before them. Using confocal microscopy we examined dividing GC B cells and observed that two drivers of GC B cell differentiation, Bcl6 and the receptor for the cytokine IL-21 (IL-21R), are asymmetrically segregated during mitosis and unequally inherited by the resulting daughter B cells. This process is dependent on the evolutionarily conserved regulator of polarity, aPKC, and GC B cells are stimulated to divide asymmetrically by contacts made with helper T cells. By examining humoral immune responses in mice in which GC B cells do not divide asymmetrically, we have shown that asymmetric division is not required for B cell differentiation, while cell-cell contacts are absolutely critical to their differentiation. These data suggest that, in addition to signals from the environment of the GC reaction, diversity of GC B cell function may be supported by cell-cell interactions in the GC reaction.

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