Signals Controlling Peripheral B Cell Development, Selection, and Activation

Thesis (Ph.D.)--University of Washington, 2013Control of B cell development through transitional stages in the periphery is critical for the proper maintenance and selection of mature, functional B cell subsets capable of mediating humoral immunity. We have established an important role for T cells and CD40 in supporting development and selection of transitional B cells. T cells and CD40 are required for optimal B cell homeostatic proliferation in response to lymphopenia, and expression of CD40 provides a competitive advantage to B cells developing in a mixed BM chimera environment. Further, transgenic BCR models demonstrate altered BCR-specificity based selection in the absence of CD40. The combination of single-cell BCR cloning and high throughput BCR sequencing was used to determine the role of CD40 on B cell selection in a non-transgenic setting with unrestricted clonal diversity. We found altered specificity profiles of cloned BCRs and reduced BCR diversity in high throughput sequence data sets from CD40-deficient mice. In addition, a critical, B cell-intrinsic role was demonstrated for Wiskott-Aldrich syndrome protein (WASp). In the setting of B cell-specific deficiency of WASp, mice develop spontaneous autoimmune disease dependent on B cell expression of the Toll-like receptor signaling adapter MyD88. Collectively, the data presented here expand our understanding of the control of B cell development, selection, and activation in peripheral lymphoid compartments, and suggest novel methods for modulating B cell subsets in the settings of immunodeficiency and autoimmunity